MCH receptor antagonists

ABSTRACT

The present invention relates to novel compounds of the formula (I) which act as MCH receptor antagonists. These compositions are useful in pharmaceutical compositions whose use includes prophylaxis or treatment of obesity, obesity related disorders, anxiety, or depression.

This application is a 371 of PCT/US02/31059 Sep. 30, 2002, which claimspriority to United States Provisional Application 60/326463, filed Oct.1, 2001 and to United States Provisional Application 60/326758, filedOct. 2, 2001.

FIELD OF THE INVENTION

The present invention relates to compounds which act as antagonists forMCH receptors and to the use of these compounds in pharmaceuticalcompositions.

BACKGROUND OF THE INVENTION

Melanin Concentrating Hormone (MCH), a cyclic peptide, has beenidentified as the endogenous ligand of the orphan G-protein coupledreceptor SLC-1. See, for example, Shimomura et al., Biochem. Biophys.Res. Commun. 261, 622-26 (1999). Studies have indicated that MCH acts asa neurotransmitter/neuromodulator to alter a number of behavioralresponses such as feeding habits. For example, injection of MCH intorats has been reported to increase their consumption of food. Reportsindicate that genetically engineered mice which lack MCH show lower bodyweight and increased metabolism. See Saito et al., TEM, vol. 11, 299(2000). As such, the literature suggests that discovery of MCHantagonists that interact with SCL-1 expressing cells will be useful indeveloping obesity treatments. See Shimomura et al., Biochem. Biophys.Res. Commun. 261, 622-26 (1999).

G protein-coupled receptors (GPCRs) share a common structural motif. Allthese receptors have seven sequences of between 22 to 24 hydrophobicamino acids that form seven alpha helices, each of which spans themembrane. The fourth and fifth transmembrane helices are joined on theextracellular side of the membrane by a strand of amino acids that formsa relatively large loop. Another larger loop, composed primarily ofhydrophilic amino acids, joins transmembrane helices five and six on theintracellular side of the membrane. The carboxy terminus of the receptorlies intracellularly, and the amino terminus lies in the extracellularspace. It is thought that the loop joining helices five and six, as wellas the carboxy terminus, interact with the G protein. Currently, Gq, Gs,Gi, and Go are G proteins that have been identified as possible proteinsthat interact with the receptor.

Under physiological conditions, GPCRs exist in the cell membrane inequilibrium between two different states or conformations: an “inactive”state and an “active” state. A receptor in an inactive state is unableto link to the intracellular transduction pathway to produce abiological response. Changing the receptor conformation to the activestate allows linkage to the transduction pathway and produces abiological response.

A receptor may be stabilized in an active state by an endogenous ligandor an exogenous agonist ligand. Recent discoveries, including but notexclusively limited to, modifications to the amino acid sequence of thereceptor, provide alternative mechanisms other than ligands to stabilizethe active state conformation. These approaches effectively stabilizethe receptor in an active state by simulating the effect of a ligandbinding to the receptor. Stabilization by such ligand-independentapproaches is termed “constitutive receptor activation.” In contrast,antagonists can competitively bind to the receptor at the same site asagonists, but do not activate the intracellular response initiated bythe active form of the receptor, and therefore inhibit the intracellularresponses by agonists.

Certain 2-aminoquinazoline derivatives have been reported to be NPYantagonists which are said to be effective in the treatment of disordersand diseases associated with the NPY receptor subtype Y5. See WO97/20823. Quinazoline derivatives have also been found to be useful byenhancing antitumor activity. See WO 92/07844.

Recently, our current knowledge of human obesity has advanceddramatically. Previously, obesity was viewed as an oppugnant behavior ofinappropriate eating in the setting of appealing foods. Studies ofanimal models of obesity, biochemical alterations in both humans andanimals, and the complex interactions of psychosocial and culturalfactors that create receptiveness to human obesity indicate that thisdisease in humans is multifaceted and deeply entrenched in biologicsystems. Thus, it is almost certain that obesity has multiple causes andthat there are different types of obesity. Not only does MCHR1antagonist have potent and durable anti-obesity effects in rodents, ithas surprising antidepressant and anxiolytic properties as well(Borowsky et al., Nature Medicine, 8, 825-830, 2002). MCHR1 antagonistshave been reported to show antidepressant and anxiolytic activities inrodent models such as social interaction, forced swimming test andultrasonic vocalization. These findings indicate that MCHR1 antagonistscould be useful for treatment of obesity patients with multiple causes.Moreover, MCHR1 antagonists could be used to treat subjects not onlywith obesity, but also those with depression and anxiety. Theseadvantages make it different from NPY receptor antagonists, with whichanxiogenic-like activity may be expected, as NPY itself hasanxiolytic-like effect.

Obesity is also regarded as a chronic disease and the possibly oflong-term treatment is a concept that is receiving more attention. Inthis context, it is noteworthy that the depletion of MCH leads tohypophagia as well as leanness (Shimada et al., Nature, 396, 670-674,1998). By contrast, NPY (Erickson et al., Nature, 381, 415-418, 1996),as well as the Y1 (Pedrazzini et al., Nature Medicine, 4, 722-726, 1998)and Y5 receptors (Marsh et al., Nature Medicine, 4, 718-721, 1998),disrupted mice maintained a stable body weight or rather became obese.Considering the above reports, MCHR1 antagonists may be more attractivethan Y1 or Y5 receptor antagonists in terms of long-term treatment ofobese patients.

An increasing number of children and adolescents are overweight.Although not all overweight children will necessarily become overweightadults, the growing occurrence of obesity in childhood is likely to bereflected in increasing obesity in adult years. The high prevalence ofobesity in our adult population and the likelihood that the nation ofthe future will be even more obese demands a re-examination of thehealth implications of this disease. See, Health Implications ofObesity. NIH Consens. Statement Online 1985 Feb. 11-13; 5(9):1-7.

“Clinical obesity” is a measurement of the excess body fat relative tolean body mass and is defined as a body weight more than 20% above theideal body weight. Recent estimates suggest that 1 in 2 adults in theUnited States is clinically obese, an increase of more than 25% over thepast decades. Flegal M. D. et al., 22 Int. J. Obes. Relat. Metab. Disor.39 (1998). Both overweight conditions and clinical obesity are a majorhealth concerns worldwide, in particular because clinical obesity isoften accompanied by numerous complications, i.e., hypertension and TypeII diabetes, which in turn can cause coronary artery disease, stroke,late-stage complications of diabetes and premature death. (See, e.g.,Nishina P. M. et al., 43 Metab. 554 (1994)).

Although the etiologic mechanisms underlying obesity require furtherclarification, the net effect of such mechanisms leads to an imbalancebetween energy intake and expenditure. Both genetic and environmentalfactors are likely to be involved in the pathogenesis of obesity. Theseinclude excess caloric intake, decreased physical activity, andmetabolic and endocrine abnormalities.

Treatment of overweight conditions and clinical obesity viapharmaceutical agents are not only of importance with respect to theconditions themselves, but also with respect to the possibility ofpreventing other diseases that are associated with, e.g., clinicalobesity, as well as enhancement of the positive feeling of “self” thatoften accompanies those who are overweight or clinically obese and whoencounter a significant reduction in body weight. Given the foregoingdiscussion, it is apparent that compounds which help in the treatment ofsuch disorders would be useful and would provide an advance in bothresearch and clinical medicine. The present invention is directed tothese, as well as other, important ends.

SUMMARY OF THE INVENTION

The present invention, in one aspect, relates to compounds representedby Formula I:

or a pharmaceutically acceptable salt or prodrug thereof, wherein Q is

R₁ represents

(i) C₁-C₁₆ alkyl,

C₁-C₁₆ alkyl substituted by substituent(s) independently selected from

-   -   halogen,    -   hydroxy,    -   oxo,    -   C₁-C₃ alkoxy,    -   C₁-C₃ alkoxy substituted by substituent(s) independently        selected from        -   carbocyclic aryl,        -   heterocyclyl,        -   heterocyclyl substituted by C₁-C₃ alkyl,    -   C₁-C₃ alkylcarbonyloxy,    -   carbocyclyloxy,    -   carbocyclic aryloxy,    -   carbocyclic aryloxy substituted by substituent(s) independently        selected from        -   halogen,        -   nitro,        -   carbocyclic aryl,        -   carbocyclic aryl substituted by C₁-C₃ alkoxy,        -   C₁-C₄ alkyl,        -   C₁-C₄ alkyl substituted by substituent(s) independently            selected from            -   oxo,            -   mono- or di-C₁-C₃ alkylamino,            -   mono- or di-C₁-C₃ alkylamino substituted by carbocyclic                aryl,            -   mono- or di-C₁-C₃ alkylamino substituted by halogenated                carbocyclic aryl,            -   carbocyclic arylcarbonylamino,            -   halogenated carbocyclic arylcarbonylamino,    -   heterocyclyloxy,    -   heterocyclyloxy substituted by C₁-C₃ alkyl,    -   substituted heterocyclyl-ethylideneaminooxy,    -   C₁-C₃ alkoxycarbonyl,    -   C₁-C₃ alkoxycarbonyl substituted by carbocyclic aryl,    -   mono- or di-C₁-C₃ alkylaminocarbonyl,    -   mono- or di-C₁-C₃ alkylamino,    -   mono- or di-C₁-C₃ alkylamino substituted by substituent(s)        independently selected from        -   cyano,        -   carbocyclic aryl,        -   heterocyclyl,    -   mono- or di-carbocyclic arylamino,    -   mono- or di-carbocyclic arylamino substituted by substituent(s)        independently selected from        -   hydroxy,        -   C₁-C₃ alkyl,    -   C₁-C₃ alkylcalbonylamino,    -   C₁-C₃ alkylcalbonylamino substituted by substituent(s)        independently selected from        -   C₁-C₃ alkylcalbonylamino,        -   carbocyclic arylcalbonylamino,        -   heterocyclyl,    -   C₁-C₄ alkoxycalbonylamino,    -   heterocyclyl calbonylamino,    -   carbocyclic arylsulfonylamino,    -   carbocyclic arylsulfonylamino substituted by substituent(s)        independently selected from        -   nitro,        -   C₁-C₃ alkyl,        -   mono- or di-C₁-C₃ alkylamino,    -   C₁-C₃ alkylthio,    -   C₁-C₃ alkylthio substituted by substituent(s) independently        selected from        -   mono- or di-carbocyclic arylaminocarbonyl,        -   halogenated mono- or di-carbocyclic arylaminocarbonyl,        -   mono- or di-carbocyclic arylamino,        -   halogenated mono- or di-carbocyclic arylamino,        -   carbocyclic aryl,        -   carbocyclic aryl substituted by substituent(s) independently            selected from            -   halogen,            -   C₁-C₃ alkoxy,    -   carbocyclic arylthio,    -   carbocyclic arylthio substituted by substituent(s) independently        selected from        -   halogen,        -   C₁-C₃ alkyl,    -   carbocyclic arylsulfonyl,    -   halogenated carbocyclic arylsulfonyl,    -   heterocyclylthio,    -   heterocyclylthio substituted by substituent(s) independently        selected from        -   nitro,        -   C₁-C₃ alkyl,    -   C₃-C₆ cycloalkyl,    -   C₃-C₆ cycloalkyl substituted by C₁-C₃ alkyl,    -   C₃-C₆ cycloalkenyl,    -   carbocyclyl,    -   carbocyclyl substituted by substituent(s) independently selected        from        -   halogen,        -   C₁-C₃ alkyl,        -   C₁-C₃ alkoxy,        -   C₂-C₃ alkenyl,        -   C₂-C₃ alkenyl substituted by carbocyclic aryl,        -   C₂-C₃ alkenyl substituted by carbocyclic aryl substituted            C₁-C₃ alkylsulfinyl,    -   carbocyclic aryl,    -   carbocyclic aryl substituted by substituent(s) independently        selected from        -   halogen,        -   hydroxy,        -   nitro,        -   C₁-C₄ alkyl,        -   C₁-C₄ alkyl substituted by substituent(s) independently            selected from            -   halogen,            -   hydroxy,            -   oxo            -   carbocyclic aryl,            -   heterocyclyl,            -   mono- or di-carbocyclic arylamino,            -   mono- or di-carbocyclic arylamino substituted by                substituent(s) independently selected from                -   halogen,                -   nitro,                -   C₁-C₃ alkyl,                -   C₁-C₃ alkoxy,                -   halogenated C₁-C₃ alkoxy,        -   C₁-C₄ alkoxy,        -   C₁-C₄ alkoxy substituted by substituent(s) independently            selected from            -   halogen,            -   carbocyclic aryl,        -   carbocyclic aryloxy,        -   C₁-C₃ alkoxycarbonyl,        -   C₁-C₃ alkylcarbonyloxy,        -   mono- or di-C₁-C₃ alkylamino,        -   mono- or di-carbocyclic arylamino,        -   halogenated mono- or di-carbocyclic arylamino,        -   mono- or di-carbocyclic arylaminocarbonyl,        -   mono- or di-carbocyclic arylaminocarbonyl substituted by            substituent(s) independently selected from            -   halogen,            -   nitro,            -   C₁-C₃ alkyl,            -   C₁-C₃ alkoxy,            -   halogenated C₁-C₃ alkoxy,        -   mercapto,        -   C₁-C₃ alkylthio,        -   halogenated C₁-C₃ alkylthio,        -   C₁-C₃ alkylsulfonyl,        -   C₃-C₆ cycloalkyl,        -   carbocyclic aryl,        -   heterocyclyl,    -   heterocyclyl,    -   heterocyclyl substituted by substituent(s) independently        selected from        -   hydroxy,        -   C₁-C₃ alkyl,        -   C₁-C₃ alkyl substituted by carbocyclic aryl,        -   C₁-C₃ alkoxy,        -   C₁-C₃ alkoxy substituted by carbocyclic aryl,        -   carbocyclic aryl,        -   halogenated carbocyclic aryl,            (ii) C₂-C₈ alkenyl,            C₂-C₈ alkenyl substituted by substituent(s) independently            selected from    -   halogen,    -   oxo,    -   C₁-C₃ alkoxy,    -   C₁-C₃ alkoxy substituted by carbocyclic aryl,    -   carbocyclic aryl,    -   carbocyclic aryl substituted by substituent(s) independently        selected from        -   halogen,        -   hydroxy,        -   nitro,        -   C₁-C₃ alkyl,        -   halogenated C₁-C₃ alkyl,        -   C₁-C₃ alkoxy,        -   halogenated C₁-C₃ alkoxy,    -   heterocyclyl,    -   heterocyclyl substituted by substituent(s) independently        selected from        -   hydroxy,        -   nitro,        -   C₁-C₃ alkyl,        -   C₁-C₃ alkoxy,            (iii) C₂-C₄ alkynyl,            C₂-C₄ alkynyl substituted by carbocyclic aryl,            (iv) C₃-C₆ cycloalkyl,            C₃-C₆ cycloalkyl substituted by substituent(s) independently            selected from    -   C₁-C₃ alkyl,    -   C₁-C₃ alkyl substituted by substituent(s) independently selected        from        -   hydroxy,        -   oxo,        -   carbocyclic aryl,    -   mono- or di-C₁-C₃ alkylamino,    -   mono- or di-C₁-C₃ alkylamino substituted by carbocyclic aryl,    -   carbocyclic arylcarbonylamino,    -   carbocyclic aryl,        (v) C₃-C₆ cycloalkeyl,        C₃-C₆ cycloalkeyl substituted by C₁-C₃ alkyl,        (vi) carbocyclyl,        carbocyclyl substituted by substituent(s) independently selected        from    -   hydroxy,    -   nitro,        (vii) carbocyclic aryl,        carbocyclic aryl substituted by substituent(s) independently        selected from    -   halogen,    -   hydroxy,    -   cyano,    -   nitro,    -   C₁-C₉ alkyl,    -   C₁-C₉ alkyl substituted by substituent(s) independently selected        from        -   halogen,        -   hydroxy,        -   oxo,        -   C₁-C₃ alkoxy,        -   carbocyclic aryloxy,        -   mono- or di-C₁-C₃ alkylamino-N-oxy,        -   mono- or di-C₁-C₃ alkylamino,        -   mono- or di-C₁-C₃ alkylamino substituted by carbocyclic            aryl,        -   mono- or di-carbocyclic arylamino,        -   carbocyclylimino,        -   carbocyclylimino substituted by carbocyclic aryl,        -   mono- or di-carbocyclic arylamino,        -   mono- or di-carbocyclic arylamino substituted by C₁-C₃            alkoxy,        -   mono- or di-carbocyclic arylaminocarbonyl,        -   mono- or di-carbocyclic arylaminocarbonyl substituted by            C₁-C₃ alkoxy,        -   carbocyclic aryl,        -   carbocyclic aryl substituted by substituent(s) independently            selected from            -   halogen,            -   C₁-C₃ alkyl,            -   halogenated C₁-C₃ alkyl,        -   heterocyclyl,        -   heterocyclyl substituted by C₁-C₃ alkyl,    -   C₂-C₃ alkenyl,    -   C₂-C₃ alkenyl substituted by carbocyclic aryl,    -   C₁-C₉ alkoxy,    -   C₁-C₉ alkoxy substituted by substituent(s) independently        selected from        -   hydroxy,        -   halogen,        -   carboxy,        -   mono- or di-C₁-C₃ alkylamino,        -   carbocyclic aryl,        -   halogenated carbocyclic aryl,        -   heterocyclyl,        -   heterocyclyl substituted by substituent(s) independently            selected from            -   halogen,            -   heterocyclyl,            -   heterocyclyl substituted by substituent(s) independently                selected from                -   halogen,                -   C₁-C₃ alkyl,                -   halogenated C₁-C₃ alkyl,    -   C₂-C₃ alkenyloxy,    -   C₁-C₃ alkylcarbonyloxy,    -   carbocyclic aryloxy,    -   carbocyclic aryloxy substituted by substituent(s) independently        selected from        -   halogen,        -   nitro,        -   C₁-C₄ alkyl,        -   halogenated C₁-C₄ alkyl,        -   C₁-C₃ alkoxy,    -   heterocyclyloxy,    -   heterocyclyloxy substituted by substituent(s) independently        selected from        -   halogen,        -   C₁-C₃ alkyl,        -   halogenated C₁-C₃ alkyl,    -   (carbocyclic aryl)S(O)₂O,    -   carboxy,    -   C₁-C₃ alkoxycarbonyl,    -   mono- or di-C₁-C₃ alkylaminocarbonyl,    -   mono- or di-C₁-C₃ alkylaminocarbonyl substituted by carbocyclic        aryl,    -   mono- or di-carbocyclic arylaminocarbonyl,    -   mono- or di-carbocyclic arylaminocarbonyl substituted by C₁-C₃        alkyl,    -   amino,    -   mono- or di-C₁-C₄ alkylamino,    -   mono- or di-C₁-C₄ alkylamino substituted by cyano,    -   mono- or di-carbocyclic arylamino,    -   C₁-C₃ alkynylcarbonylamino,    -   C₁-C₃ alkynylcarbonylamino substituted by carbocyclic aryl,    -   carbocyclic arylsulfonylamino,    -   carbocyclic arylsulfonylamino substituted by C₁-C₃ alkyl,    -   (carbocyclic aryl)NHC(O)NH,    -   (carbocyclic aryl)NHC(O)NH substituted by C₁-C₃ alkoxy,    -   (carbocyclic aryl)NHC(O)NH substituted by haloganated C₁-C₃        alkoxy,    -   carbocyclic aryl diazo,    -   carbocyclic aryl diazo substituted by mono- or di-C₁-C₃        alkylamino,    -   C₁-C₃ alkylthio,    -   halogenated C₁-C₃ alkylthio,    -   carbocyclic arylthio,    -   carbocyclic arylthio substituted by substituent(s) independently        selected from        -   halogen,        -   cyano,        -   C₁-C₃ alkyl,    -   heterocyclylthio,    -   C₁-C₃ alkylsulfonyl,    -   mono- or di-C₁-C₃ alkylaminosulfonyl,    -   carbocyclic aryl,    -   carbocyclic aryl substituted by substituent(s) independently        selected from        -   C₁-C₇ alkyl,        -   halogenated C₁-C₇ alkyl,    -   heterocyclyl,    -   heterocyclyl substituted by substituent(s) independently        selected from        -   C₁-C₃ alkyl,        -   carbocyclic aryl,        -   halogenated carbocyclic aryl,            (viii) heterocyclyl,            or heterocyclyl substituted by substituent(s) independently            selected from    -   halogen,    -   hydroxy,    -   cyano,    -   nitro,    -   C₁-C₄ alkyl,    -   C₁-C₄ alkyl substituted by substituent(s) independently selected        from        -   halogen,        -   hydroxy,        -   oxo,        -   C₁-C₃ alkylcarbonyloxy,        -   carbocyclic arylcarbonylamino,        -   halogenated carbocyclic arylcarbonylamino,        -   C₁-C₃ alkoxycarbonyl,        -   C₁-C₃ alkylthio,        -   C₁-C₃ alkylthio substituted by carbocyclic aryl,        -   C₁-C₃ alkylthio substituted by halogenated carbocyclic aryl,        -   carbocyclic aryl,        -   carbocyclic aryl substituted by substituent(s) independently            selected from            -   halogen,            -   nitro,        -   heterocyclyl,        -   heterocyclyl substituted by substituent(s) independently            selected from            -   halogen,            -   C₁-C₃ alkyl,            -   halogenated C₁-C₃ alkyl,    -   C₁-C₃ alkoxy,    -   C₁-C₃ alkoxy substituted by carbocyclic aryl,    -   carbocyclic aryloxy,    -   carbocyclic aryloxy substituted by substituent(s) independently        selected from        -   halogen,        -   C₁-C₃ alkyl,    -   mono- or di-C₁-C₃ alkylamino,    -   C₁-C₄ alkylcarbonylamino,    -   C₁-C₃ alkylthio,    -   C₁-C₃ alkenylthio,    -   carbocyclic arylthio,    -   halogenated carbocyclic arylthio,    -   carbocyclic arylthio substituted by C₁-C₃ alkoxycarbonyl,    -   heterocyclylthio,    -   heterocyclylthio substituted by C₁-C₃ alkyl,    -   C₁-C₃ alkylsulfonyl,    -   carbocyclic arylsulfonyl,    -   halogenated carbocyclic arylsulfonyl,    -   carbocyclic arylsulfonyl substituted by C₁-C₄ alkyl,    -   C₁-C₃ alkoxycarbonyl,    -   carbocyclic aryl,    -   carbocyclic aryl substituted by substituent(s) independently        selected from        -   halogen,        -   nitro,        -   C₁-C₃ alkyl,        -   halogenated C₁-C₃ alkyl,        -   C₁-C₃ alkoxy,        -   halogenated C₁-C₃ alkoxy,    -   heterocyclyl,    -   heterocyclyl substituted by substituent(s) independently        selected from        -   halogen,        -   C₁-C₃ alkyl,        -   halogenated C₁-C₃ alkyl,        -   C₁-C₃ alkoxy,        -   C₁-C₃ alkoxycarbonyl;

R₂ is —NHNH₂, —NHNHBoc, —N(R_(2a))(R_(2b)), morpholino,4-acetyl-piperazyl, or 4-phenyl-piperazyl;

wherein R_(2a) is H or C₁-C₃ alkyl;

R_(2b) is C₁-C₄ alkyl, C₁-C₄ alkyl substituted by substituent(s)independently selected from

-   -   hydroxy,    -   C₁-C₃ alkoxy,    -   amino,    -   —NHBoc,    -   C₃-C₆ cycloalkyl,    -   carbocyclic aryl,    -   carbocyclic aryl substituted by substituent(s) independently        selected from        -   halogen,        -   C₁-C₃ alkyl,        -   C₁-C₃ alkoxy,        -   —SO₂NH₂,    -   heterocyclyl,        C₃-C₆ cycloalkyl, carbocyclic aryl, carbocyclic aryl substituted        by substituent(s) independently selected from    -   halogen,    -   C₁-C₃ alkyl,    -   C₁-C₃ alkoxy,        or a group of Formula IV;

wherein Boc is carbamic acid tert-butyl ester and R₃ is C₁-C₃ alkyl orC₁-C₃ alkyl substituted by substituent(s) independently selected from

-   -   carbocyclic aryl,    -   halogenated carbocyclic aryl,    -   carbocyclic aryl substituted by C₁-C₃ alkoxy;

L is selected from Formula V-XIX;

wherein R₄ is H or C₁-C₃ alkyl;

R₅ is H, C₁-C₃ alkyl, or C₁-C₃ alkyl substituted by a substitutedcarbocyclic aryl;

Y is —S(O)₂—, —C(O)—, or —(CH₂)_(m);

m is 0 or 1;

wherein carbocyclic aryl is phenyl, naphthyl, anthranyl, biphenyl, orphenanthryl; carbocyclyl is 10,11-dihydro-5-oxo-dibenzo[a,d]cycloheptyl,1-oxo-indanyl, 7,7-dimethyl-2-oxo-bicyclo[2.2.1]heptyl, 9H-fluorenyl,9-oxo-fluorenyl, acenaphthyl, anthraquinonyl, C-fluoren-9-ylidene,indanyl, indenyl, 1,2,3,4-tetrahydro-naphthyl, or bicyclo[2.2.1]hepteny;

heterocyclyl is 1,2,3,4-tetrahydro-isoquinolyl, 1,2,3-thiadiazolyl,1,2,3-triazolyl, 1,2-dihydro-3-oxo-pyrazolyl, 1,3,4-thiadiazolyl,1,3-dioxo-isoindolyl, 1,3-dioxolanyl, 1H-indolyl,1H-pyrrolo[2,3-c]pyridyl, 1H-pyrrolyl, 1-oxo-3H-isobenzofuranyl,2,2′,5′,2″-terthiophenyl, 2,2′-bithiophenyl,2,3-dihydro-1-oxo-isoindolyl, 2,3-dihydro-benzo[1,4]dioxinyl,2,3-dihydro-benzofuryl, 2,4-dihydro-3-oxo-pyrazolyl, 2H-benzopyranyl,2-oxo-benzopyranyl, 2-oxo-pyrrolidinyl,3,4-dihydro-2H-benzo[1,4]oxazinyl,3,4-dihydro-2H-benzo[b][1,4]dioxepinyl, 4H-benzo[1,3]dioxinyl,4H-benzopyranyl, 4-oxo-1,5,6,7-tetrahydro-indolyl,4-oxo-3,4-dihydro-phthalazinyl, 4-oxo-benzopyranyl,9,10,10-trioxo-thioxanthenyl, 9H-carbazolyl, 9H-xanthenyl, azetidinyl,benzimidazolyl, benzo[1,3]dioxolyl, benzo[2,1,3]oxadiazolyl,benzo[b]thienyl, benzofuryl, benzothiazolyl, cinnolyl, furyl,imidazo[2,1-b]thiazolyl, imidazolyl, isoxazolyl, morpholino,morpholinyl, oxazolyl, oxolanyl, piperazyl, piperidyl, piridyl,pyrazolo[5,1-b]thiazolyl, pyrazolyl, pyridyl, pyrimidyl, pyrrolidyl,quinolyl, quinoxalyl, thiazolidyl, thiazolyl, thienyl, thiolanyl,2,3-dihydro-benzofuryl, tetrahydro-thienyl, or benzofuranyl;

halogen is fluoro, chloro, bromo, or iodo.

Preferred compounds of this invention are those compounds of Formula Iwherein,

Q is Formula II;

R₁ represents

(i) C₁-C₁₀ alkyl,

C₁-C₁₀ alkyl substituted by substituent(s) independently selected from

-   -   halogen,    -   oxo,    -   C₁-C₃ alkoxy,    -   C₁-C₃ alkoxy substituted by carbocyclic aryl,    -   C₁-C₃ alkylcarbonyloxy,    -   carbocyclyloxy,    -   carbocyclic aryloxy,    -   carbocyclic aryloxy substituted by substituent(s) independently        selected from        -   halogen,        -   nitro,        -   C₁-C₄ alkyl,        -   C₁-C₄ alkyl substituted by substituent(s) independently            selected from            -   oxo,            -   carbocyclic arylcarbonylamino,            -   halogenated carbocyclic arylcarbonylamino,    -   heterocyclyloxy,    -   heterocyclyloxy substituted by C₁-C₃ alkyl,    -   substituted heterocyclyl-ethylideneaminooxy,    -   C₁-C₃ alkoxycarbonyl,    -   C₁-C₃ alkoxycarbonyl substituted by carbocyclic aryl,    -   mono- or di-C₁-C₃ alkylaminocarbonyl,    -   mono- or di-carbocyclic arylamino,    -   mono- or di-carbocyclic arylamino substituted by hydroxy,    -   C₁-C₃ alkylcalbonylamino,    -   C₁-C₃ alkylcalbonylamino substituted by substituent(s)        independently selected from        -   C₁-C₃ alkylcalbonylamino,        -   carbocyclic arylcalbonylamino,        -   heterocyclyl,    -   C₁-C₄ alkoxycalbonylamino,    -   heterocyclyl calbonylamino,    -   carbocyclic arylsulfonylamino,

carbocyclic arylsulfonylamino substituted by substituent(s)independently selected from

-   -   -   nitro,        -   C₁-C₃ alkyl,        -   mono- or di-C₁-C₃ alkylamino,

    -   C₁-C₃ alkylthio,

    -   C₁-C₃ alkylthio substituted by substituent(s) independently        selected from        -   mono- or di-carbocyclic arylaminocarbonyl,        -   halogenated mono- or di-carbocyclic arylaminocarbonyl,        -   carbocyclic aryl,        -   carbocyclic aryl substituted by substituent(s) independently            selected from            -   halogen,            -   C₁-C₃ alkoxy,

    -   carbocyclic arylthio,

    -   carbocyclic arylthio substituted by substituent(s) independently        selected from        -   halogen,        -   C₁-C₃ alkyl,

    -   carbocyclic arylsulfonyl,

    -   halogenated carbocyclic arylsulfonyl,

    -   heterocyclylthio,

    -   heterocyclylthio substituted by substituent(s) independently        selected from        -   nitro,        -   C₁-C₃ alkyl,

    -   C₃-C₆ cycloalkyl,

    -   C₃-C₆ cycloalkyl substituted by C₁-C₃ alkyl,

    -   C₃-C₆ cycloalkenyl,

    -   carbocyclyl,

    -   carbocyclyl substituted by substituent(s) independently selected        from        -   halogen,        -   C₁-C₃ alkyl,        -   C₁-C₃ alkoxy,        -   C₂-C₃ alkenyl,        -   C₂-C₃ alkenyl substituted by carbocyclic aryl,        -   C₂-C₃ alkenyl substituted by carbocyclic aryl substituted            C₁-C₃ alkylsulfinyl,

    -   carbocyclic aryl,

    -   carbocyclic aryl substituted by substituent(s) independently        selected from        -   halogen,        -   hydroxy,        -   nitro,        -   C₁-C₄ alkyl,        -   C₁-C₄ alkyl substituted by substituent(s) independently            selected from            -   oxo,            -   carbocyclic aryl,            -   heterocyclyl,        -   C₁-C₄ alkoxy,        -   C₁-C₄ alkoxy substituted by substituent(s) independently            selected from            -   halogen,            -   carbocyclic aryl,        -   carbocyclic aryloxy,        -   C₁-C₃ alkylcarbonyloxy,        -   mono- or di-carbocyclic arylamino,        -   halogenated mono- or di-carbocyclic arylamino,        -   mono- or di-carbocyclic arylaminocarbonyl,        -   mono- or di-carbocyclic arylaminocarbonyl substituted by            substituent(s) independently selected from            -   halogen,            -   nitro,            -   C₁-C₃ alkyl,            -   C₁-C₃ alkoxy,            -   halogenated C₁-C₃ alkoxy,        -   mercapto,        -   C₁-C₃ alkylthio,        -   halogenated C₁-C₃ alkylthio,        -   C₁-C₃ alkylsulfonyl,        -   C₃-C₆ cycloalkyl,        -   carbocyclic aryl,        -   heterocyclyl,

    -   heterocyclyl,

    -   heterocyclyl substituted by substituent(s) independently        selected from        -   hydroxy,        -   C₁-C₃ alkyl,        -   C₁-C₃ alkyl substituted by carbocyclic aryl,        -   C₁-C₃ alkoxy,        -   C₁-C₃ alkoxy substituted by carbocyclic aryl,        -   carbocyclic aryl,        -   halogenated carbocyclic aryl,            (ii) C₂-C₆ alkenyl,            C₂-C₆ alkenyl substituted by substituent(s) independently            selected from

    -   oxo,

    -   carbocyclic aryl,

    -   carbocyclic aryl substituted by substituent(s) independently        selected from        -   halogen,        -   nitro,        -   C₁-C₃ alkyl,        -   halogenated C₁-C₃ alkyl,        -   C₁-C₃ alkoxy,        -   halogenated C₁-C₃ alkoxy,

    -   heterocyclyl,

    -   heterocyclyl substituted by substituent(s) independently        selected from        -   hydroxy,        -   C₁-C₃ alkyl,        -   C₁-C₃ alkoxy,            (iii) C₃-C₆ cycloalkyl,            C₃-C₆ cycloalkyl substituted by substituent(s) independently            selected from

    -   C₁-C₃ alkyl,

    -   C₁-C₃ alkyl substituted by substituent(s) independently selected        from        -   oxo,        -   carbocyclic aryl,

    -   carbocyclic arylcarbonylamino,

    -   carbocyclic aryl,        (iv) carbocyclyl,        carbocyclyl substituted by nitro,        (v) carbocyclic aryl,        carbocyclic aryl substituted by substituent(s) independently        selected from

    -   halogen,

    -   hydroxy,

    -   cyano,

    -   nitro,

    -   C₁-C₉ alkyl,

    -   C₁-C₉ alkyl substituted by substituent(s) independently selected        from        -   halogen,        -   oxo,        -   carbocyclic aryloxy,        -   carbocyclylimino,        -   carbocyclylimino substituted by carbocyclic aryl,        -   mono- or di-carbocyclic arylaminocarbonyl,        -   mono- or di-carbocyclic arylaminocarbonyl substituted by            C₁-C₃ alkoxy,        -   carbocyclic aryl,        -   carbocyclic aryl substituted by substituent(s) independently            selected from            -   halogen,            -   C₁-C₃ alkyl,            -   halogenated C₁-C₃ alkyl,        -   heterocyclyl,        -   heterocyclyl substituted by C₁-C₃ alkyl,

    -   C₁-C₇ alkoxy,

    -   C₁-C₇ alkoxy substituted by substituent(s) independently        selected from        -   halogen,        -   carbocyclic aryl,

    -   C₁-C₃ alkylcarbonyloxy,

    -   carbocyclic aryloxy,

    -   carbocyclic aryloxy substituted by C₁-C₃ alkoxy,

    -   C₁-C₃ alkoxycarbonyl,

    -   mono- or di-C₁-C₃ alkylaminocarbonyl,

    -   mono- or di-C₁-C₃ alkylaminocarbonyl substituted by carbocyclic        aryl,

    -   mono- or di-carbocyclic arylaminocarbonyl,

    -   mono- or di-carbocyclic arylaminocarbonyl substituted by C₁-C₃        alkyl,

    -   amino,

    -   mono- or di-C₁-C₃ alkylamino,

    -   C₁-C₃ alkynylcarbonylamino,

    -   C₁-C₃ alkynylcarbonylamino substituted by carbocyclic aryl,

    -   carbocyclic arylsulfonylamino,

    -   carbocyclic arylsulfonylamino substituted by C₁-C₃ alkyl,

    -   (carbocyclic aryl)NHC(O)NH,

    -   (carbocyclic aryl)NHC(O)NH substituted by C₁-C₃ alkoxy,

    -   (carbocyclic aryl)NHC(O)NH substituted by haloganated C₁-C₃        alkoxy,

    -   C₁-C₃ alkylthio,

    -   halogenated C₁-C₃ alkylthio,

    -   carbocyclic arylthio,

    -   carbocyclic arylthio substituted by cyano,

    -   C₁-C₃ alkylsulfonyl,

    -   mono- or di-C₁-C₃ alkylaminosulfonyl,

    -   carbocyclic aryl,

    -   carbocyclic aryl substituted by substituent(s) independently        selected from        -   C₁-C₇ alkyl,        -   halogenated C₁-C₇ alkyl,

    -   heterocyclyl,

    -   heterocyclyl substituted by substituent(s) independently        selected from        -   C₁-C₃ alkyl,        -   carbocyclic aryl,        -   halogenated carbocyclic aryl,            (vi) heterocyclyl,            or heterocyclyl substituted by substituent(s) independently            selected from

    -   halogen,

    -   nitro,

    -   C₁-C₄ alkyl,

    -   C₁-C₄ alkyl substituted by substituent(s) independently selected        from        -   halogen,        -   oxo,        -   C₁-C₃ alkylthio,        -   C₁-C₃ alkylthio substituted by carbocyclic aryl,        -   C₁-C₃ alkylthio substituted by halogenated carbocyclic aryl,        -   carbocyclic aryl,        -   halogenated carbocyclic aryl,        -   heterocyclyl,

    -   C₁-C₃ alkoxy,

    -   carbocyclic aryloxy,

    -   carbocyclic aryloxy substituted by substituent(s) independently        selected from        -   halogen,        -   C₁-C₃ alkyl,

    -   C₁-C₃ alkylthio,

    -   C₁-C₃ alkenylthio,

    -   carbocyclic arylthio,

    -   C₁-C₃ alkylsulfonyl,

    -   carbocyclic arylsulfonyl,

    -   halogenated carbocyclic arylsulfonyl,

    -   carbocyclic arylsulfonyl substituted by C₁-C₄ alkyl,

    -   carbocyclic aryl,

    -   carbocyclic aryl substituted by substituent(s) independently        selected from        -   halogen,        -   nitro,        -   C₁-C₃ alkyl,        -   C₁-C₃ alkoxy,

    -   heterocyclyl,

    -   heterocyclyl substituted by substituent(s) independently        selected from        -   C₁-C₃ alkyl,        -   halogenated C₁-C₃ alkyl;

R₂ is —NHNH₂, —NHNHBoc, —N(R_(2a))(R_(2b)), morpholino,4-acetyl-piperazyl, or 4-phenyl-piperazyl;

wherein R_(2a) is H or C₁-C₃ alkyl;

R_(2b) is C₁-C₄ alkyl, C₁-C₄ alkyl substituted by substituent(s)independently selected from

-   -   hydroxy,    -   C₁-C₃ alkoxy,    -   amino,    -   —NHBoc,    -   C₃-C₆ cycloalkyl,    -   carbocyclic aryl,    -   carbocyclic aryl substituted by substituent(s) independently        selected from        -   halogen,        -   C₁-C₃ alkyl,        -   C₁-C₃ alkoxy,        -   —SO₂NH₂,    -   heterocyclyl,        C₃-C₆ cycloalkyl, carbocyclic aryl, carbocyclic aryl substituted        by substituent(s) independently selected from    -   halogen,    -   C₁-C₃ alkyl,    -   C₁-C₃ alkoxy,        or a group of Formula IV;

wherein Boc is carbamic acid tert-butyl ester and R₃ is C₁-C₃ alkyl orC₁-C₃ alkyl substituted by substituent(s) independently selected from

-   -   carbocyclic aryl,    -   halogenated carbocyclic aryl,    -   carbocyclic aryl substituted by C₁-C₃ alkoxy;

L is selected from Formula V-XIX;

wherein R₄ is H or C₁-C₃ alkyl;

R₅ is H, C₁-C₃ alkyl, or C₁-C₃ alkyl substituted by a substitutedcarbocyclic aryl;

Y is —C(O)—;

wherein carbocyclic aryl is phenyl, naphthyl, anthranyl, or biphenyl;

carbocyclyl is 10,11-dihydro-5-oxo-dibenzo[a,d]cycloheptyl,1-oxo-indanyl, 9H-fluorenyl, 9-oxo-fluorenyl, acenaphthyl,anthraquinonyl, C-fluoren-9-ylidene, indanyl, indenyl,1,2,3,4-tetrahydro-naphthyl, or bicyclo[2.2.1]hepteny;

heterocyclyl is 1,2,3-thiadiazolyl, 1,2,3-triazolyl,1,2-dihydro-3-oxo-pyrazolyl, 1,3-dioxo-isoindolyl, 1H-indolyl,1H-pyrrolyl, 1-oxo-3H-isobenzofuranyl, 2,3-dihydro-benzo[1,4]dioxinyl,2,3-dihydro-benzofuryl, 2,4-dihydro-3-oxo-pyrazolyl, 2H-benzopyranyl,2-oxo-benzopyranyl, 2-oxo-pyrrolidinyl,3,4-dihydro-2H-benzo[b][1,4]dioxepinyl,4-oxo-1,5,6,7-tetrahydro-indolyl, 4-oxo-3,4-dihydro-phthalazinyl,4-oxo-benzopyranyl, 9,10,10-trioxo-thioxanthenyl, 9H-xanthenyl,azetidinyl, benzimidazolyl, benzo[1,3]dioxolyl, benzo[2,1,3]oxadiazolyl,benzo[b]thienyl, cinnolyl, furyl, imidazolyl, isoxazolyl, morpholino,morpholinyl, oxazolyl, oxolanyl, piperidyl, piridyl, pyrazolyl, pyridyl,pyrimidyl, pyrrolidyl, quinolyl, quinoxalyl, thiazolidyl, thiazolyl,thienyl, thiolanyl, tetrahydro-thienyl, benzofuranyl, or benzothiazolyl;

halogen is fluoro, chloro, bromo, or iodo.

Other preferred compounds of this invention are those compounds ofFormula I wherein,

Q is Formula II;

R₁ represents

(i) C₁-C₁₀ alkyl,

C₁-C₁₀ alkyl substituted by substituent(s) independently selected from

-   -   oxo,    -   di-propylaminocarbonyl,    -   methoxy substituted by carbocyclic aryl,    -   methylcarbonyloxy,    -   carbocyclic aryloxy,    -   halogenated carbocyclic aryloxy,    -   carbocyclic aryloxy substituted by nitro,    -   heterocyclyloxy substituted by methyl,    -   substituted heterocyclyl-ethylideneaminooxy,    -   tert-butoxycarbonylamino,    -   carbocyclic arylcarbonylamino,    -   C₁-C₂ alkylthio,    -   C₁-C₂ alkylthio substituted by substituent(s) independently        selected from        -   halogenated carbocyclic aryl,        -   carbocyclic aryl substituted by methoxy,    -   carbocyclic arylthio,    -   hetrocyclylthio substituted by nitro,    -   hetrocyclylthio substituted by methyl,    -   C₅-C₆ cycloalkyl,    -   C₅-C₆ cycloalkenyl,    -   carbocyclyl substituted by substituent(s) independently selected        from        -   halogen,        -   methyl,        -   methoxy,        -   ethenyl substituted by carbocyclic aryl substituted            methylsulfinyl,    -   carbocyclic aryl,    -   carbocyclic aryl substituted by substituent(s) independently        selected from        -   halogen,        -   hydroxy,        -   nitro,        -   C₁-C₄ alkyl,        -   C₁-C₄ alkyl substituted by substituent(s) independently            selected from            -   oxo,            -   carbocyclic aryl,            -   heterocyclyl,        -   C₁-C₄ alkoxy,        -   halogenated C₁-C₄ alkoxy,        -   C₁-C₄ alkoxy substituted by carbocyclic aryl,        -   carbocyclic aryloxy,        -   halogenated mono-carbocyclic arylaminocarbonyl,        -   carbocyclic aryl,        -   heterocyclyl,    -   heterocyclyl,    -   heterocyclyl substituted by substituent(s) independently        selected from        -   C₁-C₂ alkyl,        -   C₁-C₂ substituted by carbocyclic aryl,        -   methoxy,        -   methoxy substituted by carbocyclic aryl,        -   carbocyclic aryl,        -   halogenated carbocyclic aryl,            (ii) C₂-C₃ alkenyl substituted by substituent(s)            independently selected from    -   carbocyclic aryl,    -   halogenated carbocyclic aryl,    -   carbocyclic aryl substituted by nitro,        (iii) C₃-C₆ cycloalkyl,        C₃-C₆ cycloalkyl substituted by substituent(s) independently        selected from    -   methyl substituted by oxo,    -   methyl substituted by carbocyclic aryl,    -   carbocyclic aryl,        (iv) carbocyclyl,        (v) carbocyclic aryl,        carbocyclic aryl substituted by substituent(s) independently        selected from    -   halogen,    -   hydroxy,    -   cyano,    -   nitro,    -   C₁-C₉ alkyl,    -   C₁-C₉ alkyl substituted by substituent(s) independently selected        from        -   halogen,        -   oxo,        -   carbocyclic aryl,        -   carbocyclic aryl substituted by methyl,        -   carbocyclic aryloxy,    -   C₁-C₇ alkoxy,    -   halogenated C₁-C₇ alkoxy,    -   C₁-C₇ alkoxy substituted by carbocyclic aryl,    -   methylcarbonyloxy,    -   carbocyclic aryloxy,    -   carbocyclic aryloxy substituted by methoxy,    -   amino,    -   di-methylamino,    -   propargynylcarbonylamino substituted by carbocyclic aryl,    -   carbocyclic arylsulfonylamino substituted by methyl,    -   (carbocyclic aryl)NHC(O)NH substituted by halogenated methoxy,    -   halogenated methylthio,    -   carbocyclic arylthio substituted by cyano,    -   di-propylamino sulfonyl,    -   mono- or di-ethylaminocarbonyl substituted by carbocyclic aryl,    -   carbocyclic aryl,    -   heterocyclyl substituted by methyl,    -   heterocyclyl substituted by halogenated carbocyclic aryl,        (vi) heterocyclyl,        or heterocyclyl substituted by substituent(s) independently        selected from    -   halogen,    -   nitro,    -   C₁-C₄ alkyl,    -   C₁-C₄ alkyl substituted by substituent(s) independently selected        from        -   halogen,        -   methylthio substituted by halogenated carbocyclic aryl,        -   carbocyclic aryl,        -   halogenated carbocyclic aryl,        -   heterocyclyl,    -   methoxy,    -   carbocyclic aryloxy,    -   carbocyclic aryloxy substituted by methyl,    -   C₁-C₃ alkylthio,    -   propenylthio,    -   carbocyclic arylthio,    -   C₁-C₃ alkylsulfonyl,    -   carbocyclic arylsulfonyl substituted by C₁-C₄ alkyl,    -   carbocyclic aryl,    -   halogenated carbocyclic aryl,    -   carbocyclic aryl substituted by methyl,    -   carbocyclic aryl substituted by nitro,    -   heterocyclyl;

R₂ is methylamino or dimethylamino;

L is selected from Formula Va, VIIIa, or IXa;

wherein R₄ and R₅ are independently selected from H or C₁-C₃ alkyl;

Y is —C(O)—;

wherein carbocyclic aryl is phenyl, naphthyl, anthranyl, or biphenyl;

carbocyclyl is 1-oxo-indanyl, 9-oxo-fluorenyl, indenyl, anthraquinonyl,C-fluoren-9-ylidene, 1,2,3,4-tetrahydro-naphthyl, orbicyclo[2.2.1]hepteny;

heterocyclyl is 1,2,3-thiadiazolyl, 1,2,3-triazolyl,1,2-dihydro-3-oxo-pyrazolyl, 1,3-dioxo-isoindolyl, 1H-indolyl,1H-pyrrolyl, 1-oxo-3H-isobenzofuranyl, 2,3-dihydro-benzo[1,4]dioxinyl,2,4-dihydro-3-oxo-pyrazolyl, 2H-benzopyranyl, 2-oxo-benzopyranyl,3,4-dihydro-2H-benzo[b][1,4]dioxepinyl, 4-oxo-3,4-dihydro-phthalazinyl,4-oxo-benzopyranyl, 9,10,10-trioxo-thioxanthenyl, 9H-xanthenyl,azetidinyl, benzimidazolyl, benzo[1,3]dioxolyl, benzo[2,1,3]oxadiazolyl,benzo[b]thienyl, furyl, imidazolyl, isoxazolyl, morpholino, morpholinyl,oxolanyl, piperidyl, piridyl, pyrazolyl, pyridyl, quinolyl, quinoxalyl,thiazolidyl, thiazolyl, thienyl, thiolanyl,2,3-dihydro-1-oxo-isoindolyl, 2,3-dihydro-benzofuryl,2-oxo-pyrrolidinyl, 4-oxo-1,5,6,7-tetrahydro-indolyl, cinnolyl,pyrimidyl, pyrrolidyl, tetrahydro-thienyl, benzofuranyl, orbenzothiazolyl;

halogen is fluoro, chloro, bromo, or iodo.

Other more preferred compounds of this invention are those compounds ofFormula I wherein,

Q is Formula II;

R₁ represents

(i) C₁-C₁₀ alkyl substituted by substituent(s) independently selectedfrom

-   -   oxo,    -   di-propylaminocarbonyl,    -   methoxy substituted by carbocyclic aryl,    -   methylcarbonyloxy,    -   carbocyclic aryloxy,    -   halogenated carbocyclic aryloxy,    -   carbocyclic aryloxy substituted by nitro,    -   heterocyclyloxy substituted by methyl,    -   tert-butoxycarbonylamino,    -   carbocyclic arylcarbonylamino,    -   C₁-C₂ alkylthio,    -   C₁-C₂ alkylthio substituted by substituent(s) independently        selected from        -   halogenated carbocyclic aryl,        -   carbocyclic aryl substituted by methoxy,    -   carbocyclic arylthio,    -   hetrocyclylthio substituted by nitro,    -   hetrocyclylthio substituted by methyl,    -   C₅-C₆ cycloalkenyl,    -   carbocyclyl substituted by substituent(s) independently selected        from        -   halogen,        -   methyl,        -   methoxy,        -   ethenyl substituted by carbocyclic aryl substituted            methylsulfinyl,    -   carbocyclic aryl substituted by substituent(s) independently        selected from        -   halogen,        -   hydroxy,        -   nitro,        -   C₁-C₄ alkyl,        -   C₁-C₄ alkyl substituted by substituent(s) independently            selected from            -   oxo,            -   carbocyclic aryl,            -   heterocyclyl,        -   C₁-C₄ alkoxy,        -   halogenated C₁-C₄ alkoxy,        -   C₁-C₄ alkoxy substituted by carbocyclic aryl,        -   carbocyclic aryloxy,        -   halogenated mono-carbocyclic arylaminocarbonyl,        -   carbocyclic aryl,        -   heterocyclyl,    -   heterocyclyl substituted by substituent(s) independently        selected from        -   C₁-C₂ alkyl,        -   C₁-C₂ substituted by carbocyclic aryl,        -   methoxy,        -   methoxy substituted by carbocyclic aryl,        -   carbocyclic aryl,        -   halogenated carbocyclic aryl,            (ii) C₂-C₃ alkenyl substituted by substituent(s)            independently selected from    -   carbocyclic aryl,    -   halogenated carbocyclic aryl,    -   carbocyclic aryl substituted by nitro,        (iii) C₃-C₆ cycloalkyl substituted by substituent(s)        independently selected from    -   methyl substituted by oxo,    -   methyl substituted by carbocyclic aryl,    -   carbocyclic aryl,        (iv) carbocyclyl,        (v) carbocyclic aryl substituted by substituent(s) independently        selected from    -   halogen,    -   hydroxy,    -   cyano,    -   nitro,    -   C₁-C₉ alkyl,    -   C₁-C₉ alkyl substituted by substituent(s) independently selected        from        -   halogen,        -   oxo,        -   carbocyclic aryl,        -   carbocyclic aryl substituted by methyl,        -   carbocyclic aryloxy,    -   C₁-C₇ alkoxy,    -   halogenated C₁-C₇ alkoxy,    -   C₁-C₇ alkoxy substituted by carbocyclic aryl,    -   methylcarbonyloxy,    -   carbocyclic aryloxy,    -   carbocyclic aryloxy substituted by methoxy,    -   amino,    -   di-methylamino,    -   propargynylcarbonylamino substituted by carbocyclic aryl,    -   carbocyclic arylsulfonylamino substituted by methyl,    -   (carbocyclic aryl)NHC(O)NH substituted by halogenated methoxy,    -   halogenated methylthio,    -   carbocyclic arylthio substituted by cyano,    -   di-propylamino sulfonyl,    -   mono- or di-ethylaminocarbonyl substituted by carbocyclic aryl,    -   carbocyclic aryl,    -   heterocyclyl substituted by methyl,    -   heterocyclyl substituted by halogenated carbocyclic aryl,        (vi) or heterocyclyl substituted by substituent(s) independently        selected from    -   halogen,    -   nitro,    -   C₁-C₄ alkyl,    -   C₁-C₄ alkyl substituted by substituent(s) independently selected        from        -   halogen,        -   methylthio substituted by halogenated carbocyclic aryl,        -   carbocyclic aryl,        -   halogenated carbocyclic aryl,        -   heterocyclyl,    -   methoxy,    -   carbocyclic aryloxy,    -   carbocyclic aryloxy substituted by methyl,    -   C₁-C₃ alkylthio,    -   propenylthio,    -   carbocyclic arylthio,    -   C₁-C₃ alkylsulfonyl,    -   carbocyclic arylsulfonyl,    -   carbocyclic arylsulfonyl substituted by C₁-C₄ alkyl,    -   carbocyclic aryl,    -   halogenated carbocyclic aryl,    -   carbocyclic aryl substituted by methyl,    -   carbocyclic aryl substituted by nitro,    -   heterocyclyl;

R₂ is methylamino or dimethylamino;

L is selected from Formula XX-XXII;

Y is —C(O)—;

wherein carbocyclic aryl is phenyl, naphthyl, or biphenyl;

carbocyclyl is 1-oxo-indanyl, 9-oxo-fluorenyl, indenyl, anthraquinonyl,C-fluoren-9-ylidene, 1,2,3,4-tetrahydro-naphthyl, orbicyclo[2.2.1]hepteny;

heterocyclyl is 1,2,3-thiadiazolyl, 1,2,3-triazolyl,1,2-dihydro-3-oxo-pyrazolyl, 1H-indolyl, 1H-pyrrolyl,2,4-dihydro-3-oxo-pyrazolyl, 2H-benzopyranyl, 4-oxo-benzopyranyl,azetidinyl, benzo[b]thienyl, furyl, isoxazolyl, morpholinyl, piperidyl,piridyl, pyrazolyl, pyridyl, quinolyl, thiazolidyl, thiazolyl, thienyl,thiolanyl, 2,3-dihydro-1-oxo-isoindolyl, 2,3-dihydro-benzofuryl,2-oxo-benzopyranyl, 2-oxo-pyrrolidinyl,4-oxo-1,5,6,7-tetrahydro-indolyl, 9H-xanthenyl, cinnolyl, imidazolyl,morpholino, pyrimidyl, pyrrolidyl, tetrahydro-thienyl, benzofuranyl, orbenzothiazolyl;

halogen is fluoro, chloro, bromo, or iodo.

Further other more preferred compounds of this invention are thosecompounds of Formula I wherein,

Q is Formula II;

R₁ represents

(i) C₁-C₅ alkyl substituted by substituent(s) independently selectedfrom

-   -   oxo,    -   di-propylaminocarbonyl,    -   methoxy substituted by carbocyclic aryl,    -   methylcarbonyloxy,    -   carbocyclic aryloxy,    -   halogenated carbocyclic aryloxy,    -   carbocyclic aryloxy substituted by nitro,    -   heterocyclyloxy substituted by methyl,    -   substituted heterocyclyl-ethylideneaminooxy,    -   tert-butoxycarbonylamino,    -   carbocyclic arylcarbonylamino,    -   C₁-C₂ alkylthio,    -   C₁-C₂ alkylthio substituted by substituent(s) independently        selected from        -   halogenated carbocyclic aryl,        -   carbocyclic aryl substituted by methoxy,    -   carbocyclic arylthio,    -   hetrocyclylthio substituted by nitro,    -   hetrocyclylthio substituted by methyl,    -   cyclohexenyl,    -   carbocyclyl substituted by substituent(s) independently selected        from        -   halogen,        -   methyl,        -   methoxy,        -   ethenyl substituted by carbocyclic aryl substituted            methylsulfinyl,    -   carbocyclic aryl substituted by substituent(s) independently        selected from        -   halogen,        -   hydroxy,        -   nitro,        -   C₁-C₄ alkyl,        -   C₁-C₄ alkyl substituted by substituent(s) independently            selected from            -   oxo,            -   carbocyclic aryl,            -   heterocyclyl,        -   C₁-C₂ alkoxy,        -   halogenated C₁-C₂ alkoxy,        -   C₁-C₂ alkoxy substituted by carbocyclic aryl,        -   carbocyclic aryloxy,        -   halogenated mono-carbocyclic arylaminocarbonyl,        -   carbocyclic aryl,        -   heterocyclyl,    -   heterocyclyl substituted by substituent(s) independently        selected from        -   C₁-C₂ alkyl,        -   C₁-C₂ substituted by carbocyclic aryl,        -   methoxy,        -   methoxy substituted by carbocyclic aryl,        -   carbocyclic aryl,        -   halogenated carbocyclic aryl,            (ii) C₂-C₃ alkenyl substituted by substituent(s)            independently selected from    -   carbocyclic aryl,    -   halogenated carbocyclic aryl,    -   carbocyclic aryl substituted by nitro,        (iii) C₃-C₆ cycloalkyl substituted by substituent(s)        independently selected from    -   methyl substituted by oxo,    -   methyl substituted by carbocyclic aryl,    -   carbocyclic aryl,        (iv) carbocyclyl,        (v) carbocyclic aryl substituted by substituent(s) independently        selected from    -   halogen,    -   hydroxy,    -   cyano,    -   nitro,    -   C₁-C₄ alkyl,    -   C₁-C₂ alkyl substituted by substituent(s) independently selected        from        -   halogen,        -   oxo,        -   carbocyclic aryl,        -   carbocyclic aryl substituted by methyl,        -   carbocyclic aryloxy,    -   C₁-C₂ alkoxy,    -   halogenated C₁-C₂ alkoxy,    -   C₁-C₂ alkoxy substituted by carbocyclic aryl,    -   methylcarbonyloxy,    -   carbocyclic aryloxy,    -   carbocyclic aryloxy substituted by methoxy,    -   amino,    -   di-methylamino,    -   propargynylcarbonylamino substituted by carbocyclic aryl,    -   carbocyclic arylsulfonylamino substituted by methyl,    -   (carbocyclic aryl)NHC(O)NH substituted by halogenated methoxy,    -   halogenated methylthio,    -   carbocyclic arylthio substituted by cyano,    -   di-propylamino sulfonyl,    -   mono- or di-ethylaminocarbonyl substituted by carbocyclic aryl,    -   carbocyclic aryl,    -   heterocyclyl substituted by methyl,    -   heterocyclyl substituted by halogenated carbocyclic aryl,        (vi) or heterocyclyl substituted by substituent(s) independently        selected from    -   halogen,    -   nitro,    -   C₁-C₄ alkyl,    -   C₁-C₄ alkyl substituted by substituent(s) independently selected        from        -   halogen,        -   methylthio substituted by halogenated carbocyclic aryl,        -   carbocyclic aryl,        -   halogenated carbocyclic aryl,        -   heterocyclyl,    -   methoxy,    -   carbocyclic aryloxy,    -   carbocyclic aryloxy substituted by methyl,    -   C₁-C₃ alkylthio,    -   propenylthio,    -   carbocyclic arylthio,    -   C₁-C₃ alkylsulfonyl,    -   carbocyclic arylsulfonyl,    -   carbocyclic arylsulfonyl substituted by methyl,    -   carbocyclic aryl,    -   halogenated carbocyclic aryl,    -   carbocyclic aryl substituted by methyl,    -   carbocyclic aryl substituted by nitro,    -   heterocyclyl;

R₂ is methylamino or dimethylamino;

L is selected from Formula XX-XXII;

Y is —C(O)—;

wherein carbocyclic aryl is phenyl, naphthyl, or biphenyl;

carbocyclyl is 1-oxo-indanyl, indenyl, 9-oxo-fluorenyl,1,2,3,4-tetrahydro-naphthyl, or bicyclo[2.2.1]hepteny;

heterocyclyl is 1H-indolyl, 2,4-dihydro-3-oxo-pyrazolyl, furyl,pyrazolyl, pyridyl, thienyl, 1,2,3-triazolyl, 1H-pyrrolyl,2,3-dihydro-1-oxo-isoindolyl, 2,3-dihydro-benzofuryl, 2H-benzopyranyl,2-oxo-benzopyranyl, 4-oxo-1,5,6,7-tetrahydro-indolyl, imidazolyl,isoxazolyl, morpholino, morpholinyl, pyrazolyl, pyrimidyl, quinolyl,thiazolyl, tetrahydro-thienyl, benzofuranyl, or benzothiazolyl;

halogen is fluoro, chloro, bromo, or iodo.

The following compounds are specially preffered;

Other more preferred compounds of this invention are those compounds ofFormula I wherein,

Q is Formula II;

R₁ represents

(i) C₁-C₁₀ alkyl,

C₁-C₁₀ alkyl substituted by substituent(s) independently selected from

-   -   C₅-C₆ cycloalkyl,    -   carbocyclic aryl,    -   heterocyclyl,        (ii) C₃-C₆ cycloalkyl,        (iii) carbocyclic aryl,        (iv) or heterocyclyl;

R₂ is methylamino or dimethylamino;

L is selected from Formula XX-XXII;

Y is —C(O)—;

wherein carbocyclic aryl is phenyl, naphthyl, anthranyl, or biphenyl;

heterocyclyl is 1,3-dioxo-isoindolyl, 1H-indolyl,1-oxo-3H-isobenzofuranyl, 2,3-dihydro-benzo[1,4]dioxinyl,3,4-dihydro-2H-benzo[b][1,4]dioxepinyl, 4-oxo-3,4-dihydro-phthalazinyl,9,10,10-trioxo-thioxanthenyl, 9H-xanthenyl, benzimidazolyl,benzo[1,3]dioxolyl, benzo[2,1,3]oxadiazolyl, benzo[b]thienyl, furyl,imidazolyl, isoxazolyl, morpholino, oxolanyl, piperidyl, pyridyl,quinoxalyl, thienyl, quinolyl, or benzothiazolyl;

halogen is fluoro, chloro, bromo, or iodo.

Further other more preferred compounds of this invention are thosecompounds of Formula I wherein,

Q is Formula II;

R₁ represents

(i) C₁-C₄ alkyl,

C₁-C₄ alkyl substituted by substituent(s) independently selected from

-   -   cyclopentyl,    -   carbocyclic aryl,    -   heterocyclyl,        (ii) carbocyclic aryl,        (iii) or heterocyclyl;

R₂ is methylamino or dimethylamino;

L is selected from Formula XX-XXII;

Y is —C(O)—;

wherein carbocyclic aryl is phenyl, naphthyl, anthranyl, or biphenyl;

heterocyclyl is 9H-xanthenyl, benzo[1,3]dioxolyl,benzo[2,1,3]oxadiazolyl, benzo[b]thienyl, thienyl, 1H-indolyl,quinoxalyl, quinolyl, or benzothiazolyl;

halogen is fluoro, chloro, bromo, or iodo.

The following compounds are specially preffered;

Preferred compounds of this invention are those compounds of Formula Iwherein,

Q is Formula II;

R₁ represents

(i) C₁-C₁₀ alkyl,

C₁-C₁₀ alkyl substituted by substituent(s) independently selected from

-   -   halogen,    -   hydroxy,    -   oxo,    -   C₁-C₃ alkoxy,    -   C₁-C₃ alkoxy substituted by substituent(s) independently        selected from        -   carbocyclic aryl,        -   heterocyclyl,        -   heterocyclyl substituted by C₁-C₃ alkyl,    -   carbocyclic aryloxy,    -   carbocyclic aryloxy substituted by substituent(s) independently        selected from        -   halogen,        -   halogen,        -   nitro,        -   carbocyclic aryl,        -   carbocyclic aryl substituted by C₁-C₃ alkoxy,        -   C₁-C₄ alkyl,        -   C₁-C₄ alkyl substituted by substituent(s) independently            selected from            -   mono- or di-C₁-C₃ alkylamino,            -   mono- or di-C₁-C₃ alkylamino substituted by carbocyclic                aryl,            -   mono- or di-C₁-C₃ alkylamino substituted by halogenated                carbocyclic aryl,    -   mono- or di-C₁-C₃ alkylamino,    -   mono- or di-C₁-C₃ alkylamino substituted by substituent(s)        independently selected from        -   cyano,        -   carbocyclic aryl,        -   heterocyclyl,    -   mono- or di-carbocyclic arylamino,    -   mono- or di-carbocyclic arylamino substituted by C₁-C₃ alkyl,    -   C₁-C₃ alkylcalbonylamino,    -   C₁-C₄ alkoxycalbonylamino,    -   carbocyclic arylsulfonylamino,    -   carbocyclic arylsulfonylamino substituted by substituent(s)        independently selected from        -   nitro,        -   C₁-C₃ alkyl,        -   mono- or di-C₁-C₃ alkylamino,    -   C₁-C₃ alkylthio,    -   C₁-C₃ alkylthio substituted by substituent(s) independently        selected from        -   mono- or di-carbocyclic arylamino,        -   halogenated mono- or di-carbocyclic arylamino,        -   carbocyclic aryl,        -   carbocyclic aryl substituted by substituent(s) independently            selected from            -   halogen,            -   C₁-C₃ alkoxy,    -   carbocyclic arylthio,    -   carbocyclic arylthio substituted by substituent(s) independently        selected from        -   halogen,        -   C₁-C₃ alkyl,    -   carbocyclic arylsulfonyl,    -   halogenated carbocyclic arylsulfonyl,    -   heterocyclylthio,    -   C₃-C₆ cycloalkyl,    -   C₃-C₆ cycloalkyl substituted by C₁-C₃ alkyl,    -   carbocyclyl,    -   carbocyclyl substituted by substituent(s) independently selected        from        -   halogen,        -   C₁-C₃ alkyl,        -   C₂-C₃ alkenyl,        -   C₂-C₃ alkenyl substituted by carbocyclic aryl,        -   C₂-C₃ alkenyl substituted by carbocyclic aryl substituted            C₁-C₃ alkylsulfinyl,    -   carbocyclic aryl,    -   carbocyclic aryl substituted by substituent(s) independently        selected from        -   halogen,        -   hydroxy,        -   nitro,        -   C₁-C₄ alkyl,        -   C₁-C₄ alkyl substituted by substituent(s) independently            selected from            -   halogen,            -   hydroxy,            -   carbocyclic aryl,            -   mono- or di-carbocyclic arylamino,            -   mono- or di-carbocyclic arylamino substituted by                substituent(s) independently selected from                -   halogen,                -   nitro,                -   C₁-C₃ alkyl,                -   C₁-C₃ alkoxy,                -   halogenated C₁-C₃ alkoxy,        -   C₁-C₃ alkoxy,        -   C₁-C₃ alkoxy substituted by substituent(s) independently            selected from            -   halogen,            -   carbocyclic aryl,        -   carbocyclic aryloxy,        -   C₁-C₃ alkoxycarbonyl,        -   mono- or di-C₁-C₃ alkylamino,        -   C₁-C₃ alkylthio,        -   halogenated C₁-C₃ alkylthio,        -   C₁-C₃ alkylsulfonyl,        -   C₃-C₆ cycloalkyl,        -   carbocyclic aryl,        -   heterocyclyl,    -   heterocyclyl,    -   heterocyclyl substituted by substituent(s) independently        selected from        -   C₁-C₃ alkyl,        -   C₁-C₃ alkoxy,        -   C₁-C₃ alkoxy substituted by carbocyclic aryl,        -   carbocyclic aryl,        -   halogenated carbocyclic aryl,            (ii) C₂-C₉ alkenyl,            C₂-C₈ alkenyl substituted by substituent(s) independently            selected from    -   halogen,    -   C₁-C₃ alkoxy,    -   C₁-C₃ alkoxy substituted by carbocyclic aryl,    -   carbocyclic aryl,    -   carbocyclic aryl substituted by substituent(s) independently        selected from        -   halogen,        -   hydroxy,        -   C₁-C₃ alkoxy,        -   halogenated C₁-C₃ alkoxy,    -   heterocyclyl,    -   heterocyclyl substituted by nitro,        (iii) C₂-C₄ alkynyl,        C₂-C₄ alkynyl substituted by carbocyclic alkyl,        (iv) C₃-C₆ cycloalkyl,        C₃-C₆ cycloalkyl substituted by substituent(s) independently        selected from    -   C₁-C₃ alkyl,    -   C₁-C₃ alkyl substituted by substituent(s) independently selected        from        -   hydroxy,        -   oxo,        -   carbocyclic aryl,    -   mono- or di-C₁-C₃ alkylamino,    -   mono- or di-C₁-C₃ alkylamino substituted by carbocyclic aryl,    -   carbocyclic aryl,        (v) C₃-C₆ cycloalkeyl,        C₃-C₆ cycloalkeyl substituted by C₁-C₃ alkyl,        (vi) carbocyclyl,        carbocyclyl substituted by substituent(s) independently selected        from    -   hydroxy,    -   nitro,        (vii) carbocyclic aryl,        carbocyclic aryl substituted by substituent(s) independently        selected from    -   halogen,    -   hydroxy,    -   cyano,    -   nitro,    -   C₁-C₉ alkyl,    -   C₁-C₉ alkyl substituted by substituent(s) independently selected        from        -   halogen,        -   hydroxy,        -   oxo,        -   C₁-C₃ alkoxy,        -   carbocyclic aryloxy,        -   mono- or di-C₁-C₃ alkylamino-N-oxy,        -   mono- or di-C₁-C₃ alkylamino,        -   mono- or di-C₁-C₃ alkylamino substituted by carbocyclic            aryl,        -   mono- or di-carbocyclic arylamino,        -   mono- or di-carbocyclic arylamino substituted by C₁-C₃            alkoxy,        -   carbocyclic aryl,        -   halogenated carbocyclic aryl,        -   heterocyclyl,        -   heterocyclyl substituted by C₁-C₃ alkyl,    -   C₂-C₃ alkenyl,    -   C₂-C₃ alkenyl substituted by carbocyclic aryl,    -   C₁-C₉ alkoxy,    -   C₁-C₉ alkoxy substituted by substituent(s) independently        selected from        -   hydroxy,        -   halogen,        -   carboxy,        -   mono- or di-C₁-C₃ alkylamino,        -   carbocyclic aryl,        -   halogenated carbocyclic aryl,        -   heterocyclyl,        -   heterocyclyl substituted by substituent(s) independently            selected from            -   heterocyclyl,            -   heterocyclyl substituted by substituent(s) independently                selected from                -   halogen,                -   C₁-C₃ alkyl,                -   halogenated C₁-C₃ alkyl,    -   C₂-C₃ alkenyloxy,    -   C₁-C₃ alkylcarbonyloxy,    -   carbocyclic aryloxy,    -   carbocyclic aryloxy substituted by substituent(s) independently        selected from        -   halogen,        -   C₁-C₄ alkyl,        -   halogenated C₁-C₄ alkyl,        -   C₁-C₃ alkoxy,    -   heterocyclyloxy,    -   heterocyclyloxy substituted by substituent(s) independently        selected from        -   halogen,        -   C₁-C₃ alkyl,        -   halogenated C₁-C₃ alkyl,    -   (carbocyclic aryl)S(O)₂O,    -   carboxy,    -   C₁-C₃ alkoxycarbonyl,    -   mono- or di-C₁-C₃ alkylaminocarbonyl,    -   mono- or di-C₁-C₃ alkylaminocarbonyl substituted by carbocyclic        aryl,    -   amino,    -   mono- or di-C₁-C₄ alkylamino,    -   mono- or di-C₁-C₄ alkylamino substituted by cyano,    -   mono- or di-carbocyclic arylamino,    -   C₁-C₃ alkylcarbonylamino,    -   carbocyclic arylsulfonylamino,    -   carbocyclic arylsulfonylamino substituted by C₁-C₃ alkyl,    -   (carbocyclic aryl)NHC(O)NH,    -   (carbocyclic aryl)NHC(O)NH substituted by C₁-C₃ alkoxy,    -   (carbocyclic aryl)NHC(O)NH substituted by haloganated C₁-C₃        alkoxy,    -   C₁-C₃ alkylthio,    -   halogenated C₁-C₃ alkylthio,    -   carbocyclic arylthio,    -   halogenated carbocyclic arylthio,    -   carbocyclic arylthio substituted by C₁-C₃ alkyl,    -   heterocyclylthio,    -   C₁-C₃ alkylsulfonyl,    -   mono- or di-C₁-C₃ alkylaminosulfonyl,    -   carbocyclic aryl,    -   carbocyclic aryl substituted by substituent(s) independently        selected from        -   C₁-C₇ alkyl,        -   halogenated C₁-C₇ alkyl,    -   heterocyclyl,    -   heterocyclyl substituted by substituent(s) independently        selected from        -   C₁-C₃ alkyl,        -   carbocyclic aryl,        -   halogenated carbocyclic aryl,            (viii) heterocyclyl,            or heterocyclyl substituted by substituent(s) independently            selected from    -   halogen,    -   hydroxy,    -   cyano,    -   nitro,    -   C₁-C₄ alkyl,    -   C₁-C₄ alkyl substituted by substituent(s) independently selected        from        -   halogen,        -   hydroxy,        -   oxo,        -   C₁-C₃ alkylcarbonyloxy,        -   C₁-C₃ alkoxycarbonyl,        -   C₁-C₃ alkylthio substituted by carbocyclic aryl,        -   C₁-C₃ alkylthio substituted by halogenated carbocyclic aryl,        -   carbocyclic aryl,        -   carbocyclic aryl substituted by substituent(s) independently            selected from            -   halogen,            -   nitro,        -   heterocyclyl,    -   C₁-C₃ alkoxy,    -   C₁-C₃ alkoxy substituted by carbocyclic aryl,    -   carbocyclic aryloxy,    -   carbocyclic aryloxy substituted by C₁-C₃ alkyl,    -   mono- or di-C₁-C₃ alkylamino,    -   C₁-C₄ alkylcarbonylamino,    -   C₁-C₃ alkylthio,    -   carbocyclic arylthio,    -   halogenated carbocyclic arylthio,    -   carbocyclic arylthio substituted by C₁-C₃ alkoxycarbonyl,    -   heterocyclylthio,    -   heterocyclylthio substituted by C₁-C₃ alkyl,    -   C₁-C₃ alkylsulfonyl,    -   carbocyclic arylsulfonyl,    -   carbocyclic arylsulfonyl substituted by C₁-C₄ alkyl,    -   C₁-C₃ alkoxycarbonyl,    -   carbocyclic aryl,    -   carbocyclic aryl substituted by substituent(s) independently        selected from        -   halogen,        -   nitro,        -   C₁-C₃ alkyl,        -   halogenated C₁-C₃ alkyl,        -   C₁-C₃ alkoxy,        -   halogenated C₁-C₃ alkoxy,    -   heterocyclyl,    -   heterocyclyl substituted by substituent(s) independently        selected from        -   C₁-C₃ alkyl,        -   halogenated C₁-C₃ alkyl,        -   C₁-C₃ alkoxy,        -   C₁-C₃ alkoxycarbonyl;

R₂ is —NHNH₂, —NHNHBoc, —N(R_(2a))(R_(2b)), morpholino,4-acetyl-piperazyl, or 4-phenyl-piperazyl;

wherein R_(2a) is H or C₁-C₃ alkyl;

R_(2b) is C₁-C₄ alkyl, C₁-C₄ alkyl substituted by substituent(s)independently selected from

-   -   hydroxy,    -   C₁-C₃ alkoxy,    -   amino,    -   —NHBoc,    -   C₃-C₆ cycloalkyl,    -   carbocyclic aryl,    -   carbocyclic aryl substituted by substituent(s) independently        selected from        -   halogen,        -   C₁-C₃ alkyl,        -   C₁-C₃ alkoxy,        -   —SO₂NH₂,    -   heterocyclyl,        C₃-C₆ cycloalkyl, carbocyclic aryl, carbocyclic aryl substituted        by substituent(s) independently selected from    -   halogen,    -   C₁-C₃ alkyl,    -   C₁-C₃ alkoxy,        or a group of Formula IV;

wherein Boc is carbamic acid tert-butyl ester and R₃ is C₁-C₃ alkyl orC₁-C₃ alkyl substituted by substituent(s) independently selected from

-   -   carbocyclic aryl,    -   halogenated carbocyclic aryl,    -   carbocyclic aryl substituted by C₁-C₃ alkoxy;

L is selected from Formula V-XIX;

wherein R₄ is H or C₁-C₃ alkyl;

R₅ is H, C₁-C₃ alkyl, or C₁-C₃ alkyl substituted by a substitutedcarbocyclic aryl;

Y is —(CH₂)_(m), m is 0 or 1;

wherein carbocyclic aryl is phenyl, naphthyl, phenanthryl, or biphenyl;

carbocyclyl is 9H-fluorenyl, 9-oxo-fluorenyl, acenaphthyl,anthraquinonyl, indanyl, or indenyl;

heterocyclyl is 1,2,3-thiadiazolyl, 1,2,3-triazolyl,1,2-dihydro-3-oxo-pyrazolyl, 1,3,4-thiadiazolyl, 1,3-dioxo-isoindolyl,1,3-dioxolanyl, 1H-indolyl, 1H-pyrrolo[2,3-c]pyridyl, 1H-pyrrolyl,2,2′,5′,2″-terthiophenyl, 2,2′-bithiophenyl,2,3-dihydro-1-oxo-isoindolyl, 2,3-dihydro-benzo[1,4]dioxinyl,2,3-dihydro-benzofuryl, 2,4-dihydro-3-oxo-pyrazolyl, 2H-benzopyranyl,2-oxo-pyrrolidinyl, 3,4-dihydro-2H-benzo[1,4]oxazinyl,3,4-dihydro-2H-benzo[b][1,4]dioxepinyl, 4H-benzo[1,3]dioxinyl,4H-benzopyranyl, 4-oxo-1,5,6,7-tetrahydro-indolyl, 4-oxo-benzopyranyl,9H-carbazolyl, 9H-xanthenyl, azetidinyl, benzimidazolyl,benzo[1,3]dioxolyl, benzo[b]thienyl, benzofuryl, benzothiazolyl, furyl,imidazo[2,1-b]thiazolyl, imidazolyl, isoxazolyl, morpholino,morpholinyl, oxolanyl, piperazyl, piperidyl, pyrazolo[5,1-b]thiazolyl,pyrazolyl, pyridyl, pyrimidyl, pyrrolidyl, quinolyl, quinoxalyl,thiazolidyl, thiazolyl, thienyl, or thiolanyl;

halogen is fluoro, chloro, bromo, or iodo.

Other preferred compounds of this invention are those compounds ofFormula I wherein,

Q is Formula II;

R₁ represents

(i) C₁-C₁₀ alkyl substituted by substituent(s) independently selectedfrom

-   -   methoxy,    -   methoxy substituted by carbocyclic aryl,    -   carbocyclic aryloxy,    -   halogenated carbocyclic aryloxy,    -   mono-C₁-C₂ alkylamino substituted by cyano,    -   mono- or di-C₁-C₂ alkylamino substituted by carbocyclic aryl,    -   mono-carbocyclic arylamino,    -   mono-carbocyclic arylamino substituted by methyl,    -   carbocyclic arylsulfonylamino substituted by methyl,    -   carbocyclic aryl,    -   carbocyclic aryl substituted by substituent(s) independently        selected from        -   halogen,        -   nitro,        -   C₁-C₄ alkyl,        -   C₁-C₄ alkyl substituted by carbocyclic aryl,        -   C₁-C₄ alkyl substituted by hydroxy,        -   C₁-C₂ alkoxy,        -   halogenated C₁-C₂ alkoxy,    -   heterocyclyl substituted by carbocyclic aryl,        (ii) C₂-C₈ alkenyl substituted by substituent(s) independently        selected from    -   methoxy substituted by carbocyclic aryl,    -   carbocyclic aryl,    -   carbocyclic aryl substituted by methoxy,        (iii) C₂-C₄ alkynyl substituted by carbocyclic aryl,        (iv) cyclohexyl substituted by carbocyclic arylmethyl,        (v) carbocyclyl,        (vi) carbocyclic aryl,        carbocyclic aryl substituted by substituent(s) independently        selected from    -   halogen,    -   hydroxy,    -   cyano,    -   amino,    -   C₁-C₉ alkyl,    -   halogenated C₁-C₉ alkyl,    -   C₁-C₉ alkoxy,    -   C₁-C₉ alkoxy substituted by substituent(s) independently        selected from        -   halogen,        -   halogenated carbocyclic aryl,    -   propenyloxy,    -   methylamino,    -   di-C₁-C₂ alkylamino,    -   di-C₁-C₂ alkylamino substituted by cyano,    -   methylthio,    -   halogenated methylthio,        (vii) heterocyclyl,        or heterocyclyl substituted by substituent(s) independently        selected from    -   halogen,    -   C₁-C₄ alkyl,    -   C₁-C₄ alkyl substituted by hydroxy,    -   C₁-C₄ alkyl substituted by carbocyclic aryl,    -   methoxy,    -   C₁-C₂ alkoxycarbonyl,    -   carbocyclic arylthio substituted by methoxycarbonyl,    -   carbocyclic aryl,    -   carbocyclic aryl substituted by substituent(s) independently        selected from        -   halogen,        -   halogenated methyl,    -   heterocyclyl;

R₂ is methylamino or dimethylamino;

L is selected from Formula Va, VIIIa, or IXa;

wherein R₄ and R₅ are independently selected from H or C₁-C₃ alkyl;

Y is —(CH₂)_(m), m is 0 or 1;

wherein carbocyclic aryl is phenyl, naphthyl, phenanthryl, or biphenyl;

carbocyclyl is 9H-fluorenyl, acenaphthyl, or anthraquinonyl;

heterocyclyl is 1,2,3-thiadiazolyl, 1,2,3-triazolyl,1,2-dihydro-3-oxo-pyrazolyl, 1,3-dioxolanyl, 1H-indolyl, 1H-pyrrolyl,2,2′,5′,2″-terthiophenyl, 2,2′-bithiophenyl,2,3-dihydro-benzo[1,4]dioxinyl, 3,4-dihydro-2H-benzo[1,4]oxazinyl,4-oxo-benzopyranyl, 9H-carbazolyl, 9H-xanthenyl, benzimidazolyl,benzo[1,3]dioxolyl, benzo[b]thienyl, benzofuryl, benzothiazolyl, furyl,imidazolyl, isoxazolyl, oxolanyl, pyrazolo[5,1-b]thiazolyl, pyrazolyl,pyridyl, pyrimidyl, quinolyl, quinoxalyl, thiazolidyl, thiazolyl,thienyl, 2H-benzopyranyl, 4H-benzo[1,3]dioxinyl, azetidinyl,imidazo[2,1-b]thiazolyl, morpholinyl, or 2,3-dihydro-benzofuryl;

halogen is fluoro, chloro, bromo, or iodo.

Other more preferred compounds of this invention are those compounds ofFormula I wherein,

Q is Formula II;

R₁ represents

(i) C₁-C₇ alkyl substituted by substituent(s) independently selectedfrom

-   -   methoxy,    -   methoxy substituted by carbocyclic aryl,    -   carbocyclic aryloxy,    -   halogenated carbocyclic aryloxy,    -   mono-ethylamino substituted by cyano,    -   di-methylamino substituted by carbocyclic aryl,    -   mono-carbocyclic arylamino,    -   mono-carbocyclic arylamino substituted by methyl,    -   carbocyclic arylsulfonylamino substituted by methyl,    -   carbocyclic aryl,    -   carbocyclic aryl substituted by substituent(s) independently        selected from        -   halogen,        -   nitro,        -   C₁-C₄ alkyl,        -   C₁-C₄ alkyl substituted by carbocyclic aryl,        -   C₁-C₄ alkyl substituted by hydroxy,        -   metoxy,        -   halogenated methoxy,    -   heterocyclyl substituted by carbocyclic aryl,        (ii) C₂-C₇ alkenyl substituted by substituent(s) independently        selected from    -   methoxy substituted by carbocyclic aryl,    -   carbocyclic aryl,    -   carbocyclic aryl substituted by methoxy,        (iii) butynyl substituted by carbocyclic aryl,        (iv) cyclohexyl substituted by carbocyclic arylmethyl,        (v) carbocyclyl,        (vi) carbocyclic aryl,        carbocyclic aryl substituted by substituent(s) independently        selected from    -   halogen,    -   hydroxy,    -   cyano,    -   amino,    -   C₁-C₂ alkyl,    -   halogenated methyl,    -   C₁-C₃ alkoxy,    -   C₁-C₃ alkoxy substituted by substituent(s) independently        selected from        -   halogen,        -   halogenated carbocyclic aryl,    -   propenyloxy,    -   di-C₁-C₂ alkylamino,    -   di-C₁-C₂ alkylamino substituted by cyano,    -   methylthio,    -   halogenated methylthio,        (vii) heterocyclyl,        or heterocyclyl substituted by substituent(s) independently        selected from    -   halogen,    -   C₁-C₃ alkyl,    -   C₁-C₃ alkyl substituted by hydroxy,    -   C₁-C₃ alkyl substituted by carbocyclic aryl,    -   methoxy,    -   ethoxycarbonyl,    -   carbocyclic arylthio substituted by methoxycarbonyl,    -   carbocyclic aryl,    -   carbocyclic aryl substituted by substituent(s) independently        selected from        -   halogen,        -   halogenated methyl,    -   heterocyclyl;

R₂ is methylamino or dimethylamino;

L is selected from Formula XX-XXII;

Y is —(CH₂)_(m), m is 0 or 1;

wherein carbocyclic aryl is phenyl, naphthyl, or biphenyl;

carbocyclyl is acenaphthyl;

heterocyclyl is 1H-indolyl, 1H-pyrrolyl, 2,3-dihydro-benzo[1,4]dioxinyl,9H-carbazolyl, benzo[1,3]dioxolyl, furyl, pyrazolyl, thienyl,4-oxo-benzopyranyl, azetidinyl, imidazo[2,1-b]thiazolyl, pyridyl,imidazolyl, 2,3-dihydro-benzofuryl, or benzo[b]thienyl;

halogen is fluoro, chloro, bromo, or iodo.

The following compounds are specially preffered;

Preferred compounds of this invention are those compounds of Formula Iwherein,

Q is Formula II;

R₁ represents

(i) C₁-C₁₆ alkyl,

C₁-C₁₆ alkyl substituted by substituent(s) independently selected from

halogen,

carbocyclyl,

carbocyclic aryl,

carbocyclic aryl substituted by substituent(s) independently selectedfrom

-   -   -   halogen,        -   nitro,        -   C₁-C₃ alkyl,        -   halogenated C₁-C₃ alkyl,            (ii) C₂-C₃ alkenyl,            C₂-C₃ alkenyl substituted by carbocyclic aryl,            (iii) carbocyclic aryl,            carbocyclic aryl substituted by substituent(s) independently            selected from

    -   halogen,

    -   cyano,

    -   nitro,

    -   C₁-C₅ alkyl,

    -   C₁-C₅ alkyl substituted by substituent(s) independently selected        from        -   halogen,        -   oxo,

    -   C₂-C₃ alkenyl,

    -   C₁-C₄ alkoxy,

    -   C₁-C₄ alkoxy substituted by substituent(s) independently        selected from        -   halogen,        -   heterocyclyl,        -   halogenated heterocyclyl,

    -   carbocyclic aryloxy,

    -   carbocyclic aryloxy substituted by substituent(s) independently        selected from        -   halogen,        -   nitro,

    -   heterocyclyloxy,

    -   heterocyclyloxy substituted by substituent(s) independently        selected from        -   halogen,        -   C₁-C₃ alkyl,        -   halogenated C₁-C₃ alkyl,

    -   C₁-C₃ alkoxycarbonyl,

    -   mono- or di-C₁-C₄ alkylamino,

    -   C₁-C₃ alkylcarbonylamino,

    -   carbocyclic aryl diazo,

    -   carbocyclic aryl diazo substituted by mono- or di-C₁-C₃        alkylamino,

    -   C₁-C₃ alkylsulfonyl,

    -   carbocyclic aryl,        (iv) heterocyclyl,        or heterocyclyl substituted by substituent(s) independently        selected from

    -   halogen,

    -   C₁-C₃ alkyl,

    -   C₁-C₃ alkyl substituted by substituent(s) independently selected        from        -   halogen,        -   oxo,        -   carbocyclic arylcarbonylamino,        -   halogenated carbocyclic arylcarbonylamino,        -   heterocyclyl,        -   heterocyclyl substituted by substituent(s) independently            selected from            -   halogen,            -   C₁-C₃ alkyl,            -   halogenated C₁-C₃ alkyl,

    -   C₁-C₃ alkoxy,

    -   C₁-C₃ alkylcarbonylamino,

    -   carbocyclic arylsulfonyl,

    -   C₁-C₃ alkoxycarbonyl,

    -   carbocyclic aryl,

    -   halogenated carbocyclic aryl,

    -   heterocyclyl,

    -   heterocyclyl substituted by substituent(s) independently        selected from        -   halogen,        -   C₁-C₃ alkyl,        -   halogenated C₁-C₃ alkyl;

R₂ is —NHNH₂, —NNHBoc, —N(R_(2a))(R_(2b)), morpholino,4-acetyl-piperazyl, or 4-phenyl-piperazyl;

wherein R_(2a) is H or C₁-C₃ alkyl;

R_(2b) is C₁-C₄ alkyl, C₁-C₄ alkyl substituted by substituent(s)independently selected from

-   -   hydroxy,    -   C₁-C₃ alkoxy,    -   amino,    -   —NHBoc,    -   C₃-C₆ cycloalkyl,    -   carbocyclic aryl,    -   carbocyclic aryl substituted by substituent(s) independently        selected from        -   halogen,        -   C₁-C₃ alkyl,        -   C₁-C₃ alkoxy,        -   —SO₂NH₂,    -   heterocyclyl,        C₃-C₆ cycloalkyl, carbocyclic aryl, carbocyclic aryl substituted        by substituent(s) independently selected from    -   halogen,    -   C₁-C₃ alkyl,    -   C₁-C₃ alkoxy,        or a group of Formula IV;

wherein Boc is carbamic acid tert-butyl ester and R₃ is C₁-C₃ alkyl orC₁-C₃ alkyl substituted by substituent(s) independently selected from

-   -   carbocyclic aryl,    -   halogenated carbocyclic aryl,    -   carbocyclic aryl substituted by C₁-C₃ alkoxy;

L is selected from Formula V-XIX;

wherein R₄ is H or C₁-C₃ alkyl;

R₅ is H, C₁-C₃ alkyl, or C₁-C₃ alkyl substituted by a substitutedcarbocyclic aryl;

Y is —S(O)₂—;

wherein carbocyclic aryl is phenyl, naphthyl, or biphenyl;

carbocyclyl is 7,7-dimethyl-2-oxo-bicyclo[2.2.1]heptyl;

heterocyclyl is 1,2,3,4-tetrahydro-isoquinolyl, 1,2,3-thiadiazolyl,1H-pyrrolyl, benzo[2,1,3]oxadiazolyl, benzo[b]thienyl, furyl,imidazolyl, isoxazolyl, pyrazolyl, pyridyl, quinolyl, thiazolyl, orthienyl;

halogen is fluoro, chloro, bromo, or iodo.

The following compounds are specially preffered;

Preferred compounds of this invention are those compounds of Formula Iwherein,

Q is Fomura II;

R₁ is selected from H, —CO₂ ^(t)Bu, or —CO₂Bn (Bn is a benzyl group);

R₂ is methylamino or dimethylamino;

L is selected from Formula XX-XXII;

Y is a single bond;

or a salt thereof.

Also provided in accordance with the present invention are methods ofmodulating G-protein receptor SLC-1 comprising contacting the SLC-1receptor with a compound of the invention.

The present invention further provides pharmaceutical compositionscontaining MCH receptor antagonists of the invention.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 provides an illustration of IP₃ production from severalnon-endogenous, constitutively activated version of MCH receptor ascompared with the endogenous version of this receptor.

DETAILED DESCRIPTION

The present invention relates to MCH receptor antagonist compounds, andmethods of modulating MCH receptors by contacting the receptors with oneor more compounds of the invention.

The term “antagonist” is intended to mean moieties that competitivelybind to the receptor at the same site as agonists (for example, theendogenous ligand), but which do not activate the intracellular responseinitiated by the active form of the receptor, and can thereby inhibitthe intracellular responses by agonists or partial agonists. Antagonistsdo not diminish the baseline intracellular response in the absence of anagonist or partial agonist. As used herein, the term “agonist” isintended to mean moieties that activate the intracellular response whenthey bind to the receptor, or enhance GTP binding to membranes. In thecontext of the present invention, a pharmaceutical compositioncomprising a MCH receptor antagonist of the invention can be utilizedfor modulating the activity of the MCH receptor, decreasing body weightand/or affecting metabolism such that the recipient loses weight and/ormaintains weight. Such pharmaceutical compositions can be used in thecontext of disorders and/or diseases where weight gain is a component ofthe disease and/or disorder such as, for example, obesity.

As used herein, the term “contact” or “contacting” shall mean bringingthe indicated moieties together, whether in an in vitro system or an invivo system. Thus, “contacting” an MCH receptor with a compound of theinvention includes the administration of a compound of the invention toan animal having an MCH receptor, as well as, for example, introducing acompound of the invention into a sample containing a cellular or morepurified preparation containing an MCH receptor.

Compounds of the invention include those having Formula I, shown below:

wherein Q can be either Foemura II or III:

R₁ represents

(i) C₁-C₁₆ alkyl,

C₁-C₁₆ alkyl substituted by substituent(s) independently selected from

-   -   halogen,    -   hydroxy,    -   oxo,    -   C₁-C₃ alkoxy,    -   C₁-C₃ alkoxy substituted by substituent(s) independently        selected from        -   carbocyclic aryl,        -   heterocyclyl,        -   heterocyclyl substituted by C₁-C₃ alkyl,    -   C₁-C₃ alkylcarbonyloxy,    -   carbocyclyloxy,    -   carbocyclic aryloxy,    -   carbocyclic aryloxy substituted by substituent(s) independently        selected from        -   halogen,        -   nitro,        -   carbocyclic aryl,        -   carbocyclic aryl substituted by C₁-C₃ alkoxy,        -   C₁-C₄ alkyl,        -   C₁-C₄ alkyl substituted by substituent(s) independently            selected from            -   oxo,            -   mono- or di-C₁-C₃ alkylamino,            -   mono- or di-C₁-C₃ alkylamino substituted by carbocyclic                aryl,            -   mono- or di-C₁-C₃ alkylamino substituted by halogenated                carbocyclic aryl,            -   carbocyclic arylcarbonylamino,            -   halogenated carbocyclic arylcarbonylamino,    -   heterocyclyloxy,    -   heterocyclyloxy substituted by C₁-C₃ alkyl,    -   substituted heterocyclyl-ethylideneaminooxy,    -   C₁-C₃ alkoxycarbonyl,    -   C₁-C₃ alkoxycarbonyl substituted by carbocyclic aryl,    -   mono- or di-C₁-C₃ alkylaminocarbonyl,    -   mono- or di-C₁-C₃ alkylamino,    -   mono- or di-C₁-C₃ alkylamino substituted by substituent(s)        independently selected from        -   cyano,        -   carbocyclic aryl,        -   heterocyclyl,    -   mono- or di-carbocyclic arylamino,    -   mono- or di-carbocyclic arylamino substituted by substituent(s)        independently selected from        -   hydroxy,        -   C₁-C₃ alkyl,    -   C₁-C₃ alkylcalbonylamino,    -   C₁-C₃ alkylcalbonylamino substituted by substituent(s)        independently selected from        -   C₁-C₃ alkylcalbonylamino,        -   carbocyclic arylcalbonylamino,        -   heterocyclyl,    -   C₁-C₄ alkoxycalbonylamino,    -   heterocyclyl calbonylamino,    -   carbocyclic arylsulfonylamino,    -   carbocyclic arylsulfonylamino substituted by substituent(s)        independently selected from        -   nitro,        -   C₁-C₃ alkyl,        -   mono- or di-C₁-C₃ alkylamino,    -   C₁-C₃ alkylthio,    -   C₁-C₃ alkylthio substituted by substituent(s) independently        selected from        -   mono- or di-carbocyclic arylaminocarbonyl,        -   halogenated mono- or di-carbocyclic arylaminocarbonyl,        -   mono- or di-carbocyclic arylamino,        -   halogenated mono- or di-carbocyclic arylamino,        -   carbocyclic aryl,        -   carbocyclic aryl substituted by substituent(s) independently            selected from            -   halogen,            -   C₁-C₃ alkoxy,    -   carbocyclic arylthio,    -   carbocyclic arylthio substituted by substituent(s) independently        selected from        -   halogen,        -   C₁-C₃ alkyl,    -   carbocyclic arylsulfonyl,    -   halogenated carbocyclic arylsulfonyl,    -   heterocyclylthio,    -   heterocyclylthio substituted by substituent(s) independently        selected from        -   nitro,        -   C₁-C₃ alkyl,    -   C₃-C₆ cycloalkyl,    -   C₃-C₆ cycloalkyl substituted by C₁-C₃ alkyl,    -   C₃-C₆ cycloalkenyl,    -   carbocyclyl,    -   carbocyclyl substituted by substituent(s) independently selected        from        -   halogen,        -   C₁-C₃ alkyl,        -   C₁-C₃ alkoxy,        -   C₂-C₃ alkenyl,        -   C₂-C₃ alkenyl substituted by carbocyclic aryl,        -   C₂-C₃ alkenyl substituted by carbocyclic aryl substituted            C₁-C₃ alkylsulfinyl,    -   carbocyclic aryl,    -   carbocyclic aryl substituted by substituent(s) independently        selected from        -   halogen,        -   hydroxy,        -   nitro,        -   C₁-C₄ alkyl,        -   C₁-C₄ alkyl substituted by substituent(s) independently            selected from            -   halogen,            -   hydroxy,            -   oxo,            -   carbocyclic aryl,            -   heterocyclyl,            -   mono- or di-carbocyclic arylamino,            -   mono- or di-carbocyclic arylamino substituted by                substituent(s) independently selected from                -   halogen,                -   nitro,                -   C₁-C₃ alkyl,                -   C₁-C₃ alkoxy,                -   halogenated C₁-C₃ alkoxy,        -   C₁-C₄ alkoxy,        -   C₁-C₄ alkoxy substituted by substituent(s) independently            selected from            -   halogen,            -   carbocyclic aryl,        -   carbocyclic aryloxy,        -   C₁-C₃ alkoxycarbonyl,        -   C₁-C₃ alkylcarbonyloxy,        -   mono- or di-C₁-C₃ alkylamino,        -   mono- or di-carbocyclic arylamino,        -   halogenated mono- or di-carbocyclic arylamino,        -   mono- or di-carbocyclic arylaminocarbonyl,        -   mono- or di-carbocyclic arylaminocarbonyl substituted by            substituent(s) independently selected from            -   halogen,            -   nitro,            -   C₁-C₃ alkyl,            -   C₁-C₃ alkoxy,            -   halogenated C₁-C₃ alkoxy,        -   mercapto,        -   C₁-C₃ alkylthio,        -   halogenated C₁-C₃ alkylthio,        -   C₁-C₃ alkylsulfonyl,        -   C₃-C₆ cycloalkyl,        -   carbocyclic aryl,        -   heterocyclyl,    -   heterocyclyl,    -   heterocyclyl substituted by substituent(s) independently        selected from        -   hydroxy,        -   C₁-C₃ alkyl,        -   C₁-C₃ alkyl substituted by carbocyclic aryl,        -   C₁-C₃ alkoxy,        -   C₁-C₃ alkoxy substituted by carbocyclic aryl,        -   carbocyclic aryl,        -   halogenated carbocyclic aryl,            (ii) C₂-C₈ alkenyl,            C₂-C₈ alkenyl substituted by substituent(s) independently            selected from    -   halogen,    -   oxo,    -   C₁-C₃ alkoxy,    -   C₁-C₃ alkoxy substituted by carbocyclic aryl,    -   carbocyclic aryl,    -   carbocyclic aryl substituted by substituent(s) independently        selected from        -   halogen,        -   hydroxy,        -   nitro,        -   C₁-C₃ alkyl,        -   halogenated C₁-C₃ alkyl,        -   C₁-C₃ alkoxy,        -   halogenated C₁-C₃ alkoxy,    -   heterocyclyl,    -   heterocyclyl substituted by substituent(s) independently        selected from        -   hydroxy,        -   nitro,        -   C₁-C₃ alkyl,        -   C₁-C₃ alkoxy,            (iii) C₂-C₄ alkynyl,            C₂-C₄ alkynyl substituted by carbocyclic aryl,            (iv) C₃-C₆ cycloalkyl,            C₃-C₆ cycloalkyl substituted by substituent(s) independently            selected from    -   C₁-C₃ alkyl,    -   C₁-C₃ alkyl substituted by substituent(s) independently selected        from        -   hydroxy,        -   oxo,        -   carbocyclic aryl,    -   mono- or di-C₁-C₃ alkylamino,    -   mono- or di-C₁-C₃ alkylamino substituted by carbocyclic aryl,    -   carbocyclic arylcarbonylamino,    -   carbocyclic aryl,        (v) C₃-C₆ cycloalkeyl,        C₃-C₆ cycloalkeyl substituted by C₁-C₃ alkyl,        (vi) carbocyclyl,        carbocyclyl substituted by substituent(s) independently selected        from    -   hydroxy,    -   nitro,        (vii) carbocyclic aryl,        carbocyclic aryl substituted by substituent(s) independently        selected from    -   halogen,    -   hydroxy,    -   cyano,    -   nitro,    -   C₁-C₉ alkyl,    -   C₁-C₉ alkyl substituted by substituent(s) independently selected        from        -   halogen,        -   hydroxy,        -   oxo,        -   C₁-C₃ alkoxy,        -   carbocyclic aryloxy,        -   mono- or di-C₁-C₃ alkylamino-N-oxy,        -   mono- or di-C₁-C₃ alkylamino,        -   mono- or di-C₁-C₃ alkylamino substituted by carbocyclic            aryl,        -   mono- or di-carbocyclic arylamino,        -   carbocyclylimino,        -   carbocyclylimino substituted by carbocyclic aryl,        -   mono- or di-carbocyclic arylamino,        -   mono- or di-carbocyclic arylamino substituted by C₁-C₃            alkoxy,        -   mono- or di-carbocyclic arylaminocarbonyl,        -   mono- or di-carbocyclic arylaminocarbonyl substituted by            C₁-C₃ alkoxy,        -   carbocyclic aryl,        -   carbocyclic aryl substituted by substituent(s) independently            selected from            -   halogen,            -   C₁-C₃ alkyl,            -   halogenated C₁-C₃ alkyl,        -   heterocyclyl,        -   heterocyclyl substituted by C₁-C₃ alkyl,    -   C₂-C₃ alkenyl,    -   C₂-C₃ alkenyl substituted by carbocyclic aryl,    -   C₁-C₉ alkoxy,    -   C₁-C₉ alkoxy substituted by substituent(s) independently        selected from        -   hydroxy,        -   halogen,        -   carboxy,        -   mono- or di-C₁-C₃ alkylamino,        -   carbocyclic aryl,        -   halogenated carbocyclic aryl,        -   heterocyclyl,        -   heterocyclyl substituted by substituent(s) independently            selected from            -   halogen,            -   heterocyclyl,            -   heterocyclyl substituted by substituent(s) independently                selected from                -   halogen,                -   C₁-C₃ alkyl,                -   halogenated C₁-C₃ alkyl,    -   C₂-C₃ alkenyloxy,    -   C₁-C₃ alkylcarbonyloxy,    -   carbocyclic aryloxy,    -   carbocyclic aryloxy substituted by substituent(s) independently        selected from        -   halogen,        -   nitro,        -   C₁-C₄ alkyl,        -   halogenated C₁-C₄ alkyl,        -   C₁-C₃ alkoxy,    -   heterocyclyloxy,    -   heterocyclyloxy substituted by substituent(s) independently        selected from        -   halogen,        -   C₁-C₃ alkyl,        -   halogenated C₁-C₃ alkyl,    -   (carbocyclic aryl)S(O)₂O,    -   carboxy,    -   C₁-C₃ alkoxycarbonyl,    -   mono- or di-C₁-C₃ alkylaminocarbonyl,    -   mono- or di-C₁-C₃ alkylaminocarbonyl substituted by carbocyclic        aryl,    -   mono- or di-carbocyclic arylaminocarbonyl,    -   mono- or di-carbocyclic arylaminocarbonyl substituted by C₁-C₃        alkyl,    -   amino,    -   mono- or di-C₁-C₄ alkylamino,    -   mono- or di-C₁-C₄ alkylamino substituted by cyano,    -   mono- or di-carbocyclic arylamino,    -   C₁-C₃ alkynylcarbonylamino,    -   C₁-C₃ alkynylcarbonylamino substituted by carbocyclic aryl,    -   carbocyclic arylsulfonylamino,    -   carbocyclic arylsulfonylamino substituted by C₁-C₃ alkyl,    -   (carbocyclic aryl)NHC(O)NH,    -   (carbocyclic aryl)NHC(O)NH substituted by C₁-C₃ alkoxy,    -   (carbocyclic aryl)NHC(O)NH substituted by haloganated C₁-C₃        alkoxy,    -   carbocyclic aryl diazo,    -   carbocyclic aryl diazo substituted by mono- or di-C₁-C₃        alkylamino,    -   C₁-C₃ alkylthio,    -   halogenated C₁-C₃ alkylthio,    -   carbocyclic arylthio,    -   carbocyclic arylthio substituted by substituent(s) independently        selected from        -   halogen,        -   cyano,        -   C₁-C₃ alkyl,    -   heterocyclylthio,    -   C₁-C₃ alkylsulfonyl,    -   mono- or di-C₁-C₃ alkylaminosulfonyl,    -   carbocyclic aryl,    -   carbocyclic aryl substituted by substituent(s) independently        selected from        -   C₁-C₇ alkyl,        -   halogenated C₁-C₇ alkyl,    -   heterocyclyl,    -   heterocyclyl substituted by substituent(s) independently        selected from        -   C₁-C₃ alkyl,        -   carbocyclic aryl,        -   halogenated carbocyclic aryl,            (viii) heterocyclyl,            or heterocyclyl substituted by substituent(s) independently            selected from    -   halogen,    -   hydroxy,    -   cyano,    -   nitro,    -   C₁-C₄ alkyl,    -   C₁-C₄ alkyl substituted by substituent(s) independently selected        from        -   halogen,        -   hydroxy,        -   oxo,        -   C₁-C₃ alkylcarbonyloxy,        -   carbocyclic arylcarbonylamino,        -   halogenated carbocyclic arylcarbonylamino,        -   C₁-C₃ alkoxycarbonyl,        -   C₁-C₃ alkylthio,        -   C₁-C₃ alkylthio substituted by carbocyclic aryl,        -   C₁-C₃ alkylthio substituted by halogenated carbocyclic aryl,        -   carbocyclic aryl,        -   carbocyclic aryl substituted by substituent(s) independently            selected from            -   halogen,            -   nitro,        -   heterocyclyl,        -   heterocyclyl substituted by substituent(s) independently            selected from            -   halogen,            -   C₁-C₃ alkyl,            -   halogenated C₁-C₃ alkyl,    -   C₁-C₃ alkoxy,    -   C₁-C₃ alkoxy substituted by carbocyclic aryl,    -   carbocyclic aryloxy,    -   carbocyclic aryloxy substituted by substituent(s) independently        selected from        -   halogen,        -   C₁-C₃ alkyl,    -   mono- or di-C₁-C₃ alkylamino,    -   C₁-C₄ alkylcarbonylamino,    -   C₁-C₃ alkylthio,    -   C₁-C₃ alkenylthio,    -   carbocyclic arylthio,    -   halogenated carbocyclic arylthio,    -   carbocyclic arylthio substituted by C₁-C₃ alkoxycarbonyl,    -   heterocyclylthio,    -   heterocyclylthio substituted by C₁-C₃ alkyl,    -   C₁-C₃ alkylsulfonyl,    -   carbocyclic arylsulfonyl,    -   halogenated carbocyclic arylsulfonyl,    -   carbocyclic arylsulfonyl substituted by C₁-C₄ alkyl,    -   C₁-C₃ alkoxycarbonyl,    -   carbocyclic aryl,    -   carbocyclic aryl substituted by substituent(s) independently        selected from        -   halogen,        -   nitro,        -   C₁-C₃ alkyl,        -   halogenated C₁-C₃ alkyl,        -   C₁-C₃ alkoxy,        -   halogenated C₁-C₃ alkoxy,    -   heterocyclyl,    -   heterocyclyl substituted by substituent(s) independently        selected from        -   halogen,        -   C₁-C₃ alkyl,        -   halogenated C₁-C₃ alkyl,        -   C₁-C₃ alkoxy,        -   C₁-C₃ alkoxycarbonyl;

R₂ is —NHNH₂, —NHNHBoc, —N(R_(2a))(R_(2b)), morpholino,4-acetyl-piperazyl, or 4-phenyl-piperazyl;

wherein R_(2a) is H or C₁-C₃ alkyl;

R_(2b) is C₁-C₄ alkyl, C₁-C₄ alkyl substituted by substituent(s)independently selected from

-   -   hydroxy,    -   C₁-C₃ alkoxy,    -   amino,    -   —NHBoc,    -   C₃-C₆ cycloalkyl,    -   carbocyclic aryl,    -   carbocyclic aryl substituted by substituent(s) independently        selected from        -   halogen,        -   C₁-C₃ alkyl,        -   C₁-C₃ alkoxy,        -   —SO₂NH₂,    -   heterocyclyl,        C₃-C₆ cycloalkyl, carbocyclic aryl, carbocyclic aryl substituted        by substituent(s) independently selected from    -   halogen,    -   C₁-C₃ alkyl,    -   C₁-C₃ alkoxy,        or a group of Formula IV;

wherein Boc is carbamic acid tert-butyl ester and R₃ is C₁-C₃ alkyl orC₁-C₃ alkyl substituted by substituent(s) independently selected from

-   -   carbocyclic aryl,    -   halogenated carbocyclic aryl,    -   carbocyclic aryl substituted by C₁-C₃ alkoxy;

L is selected from Formula V-XIX;

wherein R₄ is H or C₁-C₃ alkyl;

R₅ is H, C₁-C₃ alkyl, or C₁-C₃ alkyl substituted by a substitutedcarbocyclic aryl;

Y is —S(O)₂—, —C(O)—, or —(CH₂)_(m);

m is 0 or 1;

wherein carbocyclic aryl is phenyl, naphthyl, anthranyl, biphenyl, orphenanthryl;

carbocyclyl is 10,11-dihydro-5-oxo-dibenzo [a,d]cycloheptyl,1-oxo-indanyl, 7,7-dimethyl-2-oxo-bicyclo[2.2.1]heptyl, 9H-fluorenyl,9-oxo-fluorenyl, acenaphthyl, anthraquinonyl, C-fluoren-9-ylidene,indanyl, indenyl, 1,2,3,4-tetrahydro-naphthyl, or bicyclo[2.2.1]hepteny;

heterocyclyl is 1,2,3,4-tetrahydro-isoquinolyl, 1,2,3-thiadiazolyl,1,2,3-triazolyl, 1,2-dihydro-3-oxo-pyrazolyl, 1,3,4-thiadiazolyl,1,3-dioxo-isoindolyl, 1,3-dioxolanyl, 1H-indolyl,1H-pyrrolo[2,3-c]pyridyl, 1H-pyrrolyl, 1-oxo-3H-isobenzofuranyl,2,2′,5′,2″-terthiophenyl, 2,2′-bithiophenyl,2,3-dihydro-1-oxo-isoindolyl, 2,3-dihydro-benzo[1,4]dioxinyl,2,3-dihydro-benzofuryl, 2,4-dihydro-3-oxo-pyrazolyl, 2H-benzopyranyl,2-oxo-benzopyranyl, 2-oxo-pyrrolidinyl,3,4-dihydro-2H-benzo[1,4]oxazinyl,3,4-dihydro-2H-benzo[b][1,4]dioxepinyl, 4H-benzo[1,3]dioxinyl,4H-benzopyranyl, 4-oxo-1,5,6,7-tetrahydro-indolyl,4-oxo-3,4-dihydro-phthalazinyl, 4-oxo-benzopyranyl,9,10,10-trioxo-thioxanthenyl, 9H-carbazolyl, 9H-xanthenyl, azetidinyl,benzimidazolyl, benzo[1,3]dioxolyl, benzo[2,1,3]oxadiazolyl,benzo[b]thienyl, benzofuryl, benzothiazolyl, cinnolyl, furyl,imidazo[2,1-b]thiazolyl, imidazolyl, isoxazolyl, morpholino,morpholinyl, oxazolyl, oxolanyl, piperazyl, piperidyl, piridyl,pyrazolo[5,1-b]thiazolyl, pyrazolyl, pyridyl, pyrimidyl, pyrrolidyl,quinolyl, quinoxalyl, thiazolidyl, thiazolyl, thienyl, thiolanyl,2,3-dihydro-benzofuryl, tetrahydro-thienyl, or benzofuranyl;

halogen is fluoro, chloro, bromo, or iodo.

Preferred compounds of this invention are those compounds of Formula Iwherein,

Q is Formula II;

R₁ represents

(i) C₁-C₁₀ alkyl,

C₁-C₁₀ alkyl substituted by substituent(s) independently selected from

-   -   halogen,    -   oxo,    -   C₁-C₃ alkoxy,    -   C₁-C₃ alkoxy substituted by carbocyclic aryl,    -   C₁-C₃ alkylcarbonyloxy,    -   carbocyclyloxy,    -   carbocyclic aryloxy,    -   carbocyclic aryloxy substituted by substituent(s) independently        selected from        -   halogen,        -   nitro,        -   C₁-C₄ alkyl,        -   C₁-C₄ alkyl substituted by substituent(s) independently            selected from            -   oxo,            -   carbocyclic arylcarbonylamino,            -   halogenated carbocyclic arylcarbonylamino,    -   heterocyclyloxy,    -   heterocyclyloxy substituted by C₁-C₃ alkyl,    -   substituted heterocyclyl-ethylideneaminooxy,    -   C₁-C₃ alkoxycarbonyl,    -   C₁-C₃ alkoxycarbonyl substituted by carbocyclic aryl,    -   mono- or di-C₁-C₃ alkylaminocarbonyl,    -   mono- or di-carbocyclic arylamino,    -   mono- or di-carbocyclic arylamino substituted by hydroxy,    -   C₁-C₃ alkylcalbonylamino,    -   C₁-C₃ alkylcalbonylamino substituted by substituent(s)        independently selected from        -   C₁-C₃ alkylcalbonylamino,        -   carbocyclic arylcalbonylamino,        -   heterocyclyl,    -   C₁-C₄ alkoxycalbonylamino,    -   heterocyclyl calbonylamino,    -   carbocyclic arylsulfonylamino,    -   carbocyclic arylsulfonylamino substituted by substituent(s)        independently selected from        -   nitro,        -   C₁-C₃ alkyl,        -   mono- or di-C₁-C₃ arylamino,    -   C₁-C₃ alkylthio,    -   C₁-C₃ alkylthio substituted by substituent(s) independently        selected from        -   mono- or di-carbocyclic arylaminocarbonyl,        -   halogenated mono- or di-carbocyclic arylaminocarbonyl,        -   carbocyclic aryl,        -   carbocyclic aryl substituted by substituent(s) independently            selected from            -   halogen,            -   C₁-C₃ alkoxy,    -   carbocyclic arylthio,    -   carbocyclic arylthio substituted by substituent(s) independently        selected from        -   halogen,        -   C₁-C₃ alkyl,    -   carbocyclic arylsulfonyl,    -   halogenated carbocyclic arylsulfonyl,    -   heterocyclylthio,    -   heterocyclylthio substituted by substituent(s) independently        selected from        -   nitro,        -   C₁-C₃ alkyl,    -   C₃-C₆ cycloalkyl,    -   C₃-C₆ cycloalkyl substituted by C₁-C₃ alkyl,    -   C₃-C₆ cycloalkenyl,    -   carbocyclyl,    -   carbocyclyl substituted by substituent(s) independently selected        from        -   halogen,        -   C₁-C₃ alkyl,        -   C₁-C₃ alkoxy,        -   C₂-C₃ alkenyl,        -   C₂-C₃ alkenyl substituted by carbocyclic aryl,        -   C₂-C₃ alkenyl substituted by carbocyclic aryl substituted            C₁-C₃ alkylsulfinyl,    -   carbocyclic aryl,    -   carbocyclic aryl substituted by substituent(s) independently        selected from        -   halogen,        -   hydroxy,        -   nitro,        -   C₁-C₄ alkyl,        -   C₁-C₄ alkyl substituted by substituent(s) independently            selected from            -   oxo,            -   carbocyclic aryl,            -   heterocyclyl,        -   C₁-C₄ alkoxy,        -   C₁-C₄ alkoxy substituted by substituent(s) independently            selected from            -   halogen,            -   carbocyclic aryl,        -   carbocyclic aryloxy,        -   C₁-C₃ alkylcarbonyloxy,        -   mono- or di-carbocyclic arylamino,        -   halogenated mono- or di-carbocyclic arylamino,        -   mono- or di-carbocyclic arylaminocarbonyl,        -   mono- or di-carbocyclic arylaminocarbonyl substituted by            substituent(s) independently selected from            -   halogen,            -   nitro,            -   C₁-C₃ alkyl,            -   C₁-C₃ alkoxy,            -   halogenated C₁-C₃ alkoxy,        -   mercapto,        -   C₁-C₃ alkylthio,        -   halogenated C₁-C₃ alkylthio,        -   C₁-C₃ alkylsulfonyl,        -   C₃-C₆ cycloalkyl,        -   carbocyclic aryl,        -   heterocyclyl,    -   heterocyclyl,    -   heterocyclyl substituted by substituent(s) independently        selected from        -   hydroxy,        -   C₁-C₃ alkyl,        -   C₁-C₃ alkyl substituted by carbocyclic aryl,        -   C₁-C₃ alkoxy,        -   C₁-C₃ alkoxy substituted by carbocyclic aryl,        -   carbocyclic aryl,        -   halogenated carbocyclic aryl,            (ii) C₂-C₆ alkenyl,            C₂-C₆ alkenyl substituted by substituent(s) independently            selected from    -   oxo,    -   carbocyclic aryl,    -   carbocyclic aryl substituted by substituent(s) independently        selected from        -   halogen,        -   nitro,        -   C₁-C₃ alkyl,        -   halogenated C₁-C₃ alkyl,        -   C₁-C₃ alkoxy,        -   halogenated C₁-C₃ alkoxy,    -   heterocyclyl,    -   heterocyclyl substituted by substituent(s) independently        selected from        -   hydroxy,        -   C₁-C₃ alkyl,        -   C₁-C₃ alkoxy,            (iii) C₃-C₆ cycloalkyl,            C₃-C₆ cycloalkyl substituted by substituent(s) independently            selected from    -   C₁-C₃ alkyl,    -   C₁-C₃ alkyl substituted by substituent(s) independently selected        from        -   oxo,        -   carbocyclic aryl,    -   carbocyclic arylcarbonylamino,    -   carbocyclic aryl,        (iv) carbocyclyl,        carbocyclyl substituted by nitro,        (v) carbocyclic aryl,        carbocyclic aryl substituted by substituent(s) independently        selected from    -   halogen,    -   hydroxy,    -   cyano,    -   nitro,    -   C₁-C₉ alkyl,    -   C₁-C₉ alkyl substituted by substituent(s) independently selected        from        -   halogen,        -   oxo,        -   carbocyclic aryloxy,        -   carbocyclylimino,        -   carbocyclylimino substituted by carbocyclic aryl,        -   mono- or di-carbocyclic arylaminocarbonyl,        -   mono- or di-carbocyclic arylaminocarbonyl substituted by            C₁-C₃ alkoxy,        -   carbocyclic aryl,        -   carbocyclic aryl substituted by substituent(s) independently            selected from            -   halogen,            -   C₁-C₃ alkyl,        -   halogenated C₁-C₃ alkyl,        -   heterocyclyl,        -   heterocyclyl substituted by C₁-C₃ alkyl,    -   C₁-C₇ alkoxy,    -   C₁-C₇ alkoxy substituted by substituent(s) independently        selected from        -   halogen,        -   carbocyclic aryl,    -   C₁-C₃ alkylcarbonyloxy,    -   carbocyclic aryloxy,    -   carbocyclic aryloxy substituted by C₁-C₃ alkoxy,    -   C₁-C₃ alkoxycarbonyl,    -   mono- or di-C₁-C₃ alkylaminocarbonyl,    -   mono- or di-C₁-C₃ alkylaminocarbonyl substituted by carbocyclic        aryl,    -   mono- or di-carbocyclic arylaminocarbonyl,    -   mono- or di-carbocyclic arylaminocarbonyl substituted by C₁-C₃        alkyl,    -   amino,    -   mono- or di-C₁-C₃ alkylamino,    -   C₁-C₃ alkynylcarbonylamino,    -   C₁-C₃ alkynylcarbonylamino substituted by carbocyclic aryl,    -   carbocyclic arylsulfonylamino,    -   carbocyclic arylsulfonylamino substituted by C₁-C₃ alkyl,    -   (carbocyclic aryl)NHC(O)NH,    -   (carbocyclic aryl)NHC(O)NH substituted by C₁-C₃ alkoxy,    -   (carbocyclic aryl)NHC(O)NH substituted by haloganated C₁-C₃        alkoxy,    -   C₁-C₃ alkylthio,    -   halogenated C₁-C₃ alkylthio,    -   carbocyclic arylthio,    -   carbocyclic arylthio substituted by cyano,    -   C₁-C₃ alkylsulfonyl,    -   mono- or di-C₁-C₃ alkylaminosulfonyl,    -   carbocyclic aryl,    -   carbocyclic aryl substituted by substituent(s) independently        selected from        -   C₁-C₇ alkyl,        -   halogenated C₁-C₇ alkyl,    -   heterocyclyl,    -   heterocyclyl substituted by substituent(s) independently        selected from        -   C₁-C₃ alkyl,        -   carbocyclic aryl,        -   halogenated carbocyclic aryl,            (vi) heterocyclyl,            or heterocyclyl substituted by substituent(s) independently            selected from    -   halogen,    -   nitro,    -   C₁-C₄ alkyl,    -   C₁-C₄ alkyl substituted by substituent(s) independently selected        from        -   halogen,        -   oxo,        -   C₁-C₃ alkylthio,        -   C₁-C₃ alkylthio substituted by carbocyclic aryl,        -   C₁-C₃ alkylthio substituted by halogenated carbocyclic aryl,        -   carbocyclic aryl,        -   halogenated carbocyclic aryl,        -   heterocyclyl,    -   C₁-C₃ alkoxy,    -   carbocyclic aryloxy,    -   carbocyclic aryloxy substituted by substituent(s) independently        selected from        -   halogen,        -   C₁-C₃ alkyl,    -   C₁-C₃ alkylthio,    -   C₁-C₃ alkenylthio,    -   carbocyclic arylthio,    -   C₁-C₃ alkylsulfonyl,    -   carbocyclic arylsulfonyl,    -   halogenated carbocyclic arylsulfonyl,    -   carbocyclic arylsulfonyl substituted by C₁-C₄ alkyl,    -   carbocyclic aryl,    -   carbocyclic aryl substituted by substituent(s) independently        selected from        -   halogen,        -   nitro,        -   C₁-C₃ alkyl,        -   C₁-C₃ alkoxy,    -   heterocyclyl,    -   heterocyclyl substituted by substituent(s) independently        selected from        -   C₁-C₃ alkyl,        -   halogenated C₁-C₃ alkyl;

R₂ is —NHNH₂, —NHNHBoc, —N(R_(2a))(R_(2b)), morpholino,4-acetyl-piperazyl, or 4-phenyl-piperazyl;

wherein R_(2a) is H or C₁-C₃ alkyl;

R_(2b) is C₁-C₄ alkyl, C₁-C₄ alkyl substituted by substituent(s)independently selected from

-   -   hydroxy,    -   C₁-C₃ alkoxy,    -   amino,    -   —NHBoc,    -   C₃-C₆ cycloalkyl,    -   carbocyclic aryl,    -   carbocyclic aryl substituted by substituent(s) independently        selected from        -   halogen,        -   C₁-C₃ alkyl,        -   C₁-C₃ alkoxy,        -   —SO₂NH₂,    -   heterocyclyl,        C₃-C₆ cycloalkyl, carbocyclic aryl, carbocyclic aryl substituted        by substituent(s) independently selected from    -   halogen,    -   C₁-C₃ alkyl,    -   C₁-C₃ alkoxy,        or a group of Formula IV;    -   wherein Boc is carbamic acid tert-butyl ester and R₃ is C₁-C₃        alkyl or C₁-C₃ alkyl substituted by substituent(s) independently        selected from    -   carbocyclic aryl,    -   halogenated carbocyclic aryl,    -   carbocyclic aryl substituted by C₁-C₃ alkoxy;

L is selected from Formula V-XIX;

wherein R₄ is H or C₁-C₃ alkyl;

R₅ is H, C₁-C₃ alkyl, or C₁-C₃ alkyl substituted by a substitutedcarbocyclic aryl;

Y is —C(O)—;

wherein carbocyclic aryl is phenyl, naphthyl, anthranyl, or biphenyl;

carbocyclyl is 10,11-dihydro-5-oxo-dibenzo[a,d]cycloheptyl,1-oxo-indanyl, 9H-fluorenyl, 9-oxo-fluorenyl, acenaphthyl,anthraquinonyl, C-fluoren-9-ylidene, indanyl, indenyl,1,2,3,4-tetrahydro-naphthyl, or bicyclo[2.2.1]hepteny;

heterocyclyl is 1,2,3-thiadiazolyl, 1,2,3-triazolyl,1,2-dihydro-3-oxo-pyrazolyl, 1,3-dioxo-isoindolyl, 1H-indolyl,1H-pyrrolyl, 1-oxo-3H-isobenzofuranyl, 2,3-dihydro-benzo[1,4]dioxinyl,2,3-dihydro-benzofuryl, 2,4-dihydro-3-oxo-pyrazolyl, 2H-benzopyranyl,2-oxo-benzopyranyl, 2-oxo-pyrrolidinyl,3,4-dihydro-2H-benzo[b][1,4]dioxepinyl,4-oxo-1,5,6,7-tetrahydro-indolyl, 4-oxo-3,4-dihydro-phthalazinyl,4-oxo-benzopyranyl, 9,10,10-trioxo-thioxanthenyl, 9H-xanthenyl,azetidinyl, benzimidazolyl, benzo[1,3]dioxolyl, benzo[2,1,3]oxadiazolyl,benzo[b]thienyl, cinnolyl, furyl, imidazolyl, isoxazolyl, morpholino,morpholinyl, oxazolyl, oxolanyl, piperidyl, piridyl, pyrazolyl, pyridyl,pyrimidyl, pyrrolidyl, quinolyl, quinoxalyl, thiazolidyl, thiazolyl,thienyl, thiolanyl, tetrahydro-thienyl, benzofuranyl, or benzothiazolyl;

halogen is fluoro, chloro, bromo, or iodo.

Other preferred compounds of this invention are those compounds ofFormula I wherein,

Q is Formula II;

R₁ represents

(i) C₁-C₁₀ alkyl,

C₁-C₁₀ alkyl substituted by substituent(s) independently selected from

-   -   oxo,    -   di-propylaminocarbonyl,    -   methoxy substituted by carbocyclic aryl,    -   methylcarbonyloxy,    -   carbocyclic aryloxy,    -   halogenated carbocyclic aryloxy,    -   carbocyclic aryloxy substituted by nitro,    -   heterocyclyloxy substituted by methyl,    -   substituted heterocyclyl-ethylideneaminooxy,    -   tert-butoxycarbonylamino,    -   carbocyclic arylcarbonylamino,    -   C₁-C₂ alkylthio,    -   C₁-C₂ alkylthio substituted by substituent(s) independently        selected from        -   halogenated carbocyclic aryl,        -   carbocyclic aryl substituted by methoxy,    -   carbocyclic arylthio,    -   hetrocyclylthio substituted by nitro,    -   hetrocyclylthio substituted by methyl,    -   C₅-C₆ cycloalkyl,    -   C₅-C₆ cycloalkenyl,    -   carbocyclyl substituted by substituent(s) independently selected        from        -   halogen,        -   methyl,        -   methoxy,        -   ethenyl substituted by carbocyclic aryl substituted            methylsulfinyl,    -   carbocyclic aryl,    -   carbocyclic aryl substituted by substituent(s) independently        selected from        -   halogen,        -   hydroxy,        -   nitro,        -   C₁-C₄ alkyl,        -   C₁-C₄ alkyl substituted by substituent(s) independently            selected from            -   oxo,            -   carbocyclic aryl,            -   heterocyclyl,        -   C₁-C₄ alkoxy,        -   halogenated C₁-C₄ alkoxy,        -   C₁-C₄ alkoxy substituted by carbocyclic aryl,        -   carbocyclic aryloxy,        -   halogenated mono-carbocyclic arylaminocarbonyl,        -   carbocyclic aryl,        -   heterocyclyl,    -   heterocyclyl,    -   heterocyclyl substituted by substituent(s) independently        selected from        -   C₁-C₂ alkyl,        -   C₁-C₂ substituted by carbocyclic aryl,        -   methoxy,        -   methoxy substituted by carbocyclic aryl,        -   carbocyclic aryl,        -   halogenated carbocyclic aryl,            (ii) C₂-C₃ alkenyl substituted by substituent(s)            independently selected from    -   carbocyclic aryl,    -   halogenated carbocyclic aryl,    -   carbocyclic aryl substituted by nitro,        (iii) C₃-C₆ cycloalkyl,        C₃-C₆ cycloalkyl substituted by substituent(s) independently        selected from    -   methyl substituted by oxo,    -   methyl substituted by carbocyclic aryl,    -   carbocyclic aryl,        (iv) carbocyclyl,        (v) carbocyclic aryl,        carbocyclic aryl substituted by substituent(s) independently        selected from    -   halogen,    -   hydroxy,    -   cyano,    -   nitro,    -   C₁-C₉ alkyl,    -   C₁-C₉ alkyl substituted by substituent(s) independently selected        from        -   halogen,        -   oxo,        -   carbocyclic aryl,        -   carbocyclic aryl substituted by methyl,        -   carbocyclic aryloxy,    -   C₁-C₇ alkoxy,    -   halogenated C₁-C₇ alkoxy,    -   C₁-C₇ alkoxy substituted by carbocyclic aryl,    -   methylcarbonyloxy,    -   carbocyclic aryloxy,    -   carbocyclic aryloxy substituted by methoxy,    -   amino,    -   di-methylamino,    -   propargynylcarbonylamino substituted by carbocyclic aryl,    -   carbocyclic arylsulfonylamino substituted by methyl,    -   (carbocyclic aryl)NHC(O)NH substituted by halogenated methoxy,    -   halogenated methylthio,    -   carbocyclic arylthio substituted by cyano,    -   di-propylamino sulfonyl,    -   mono- or di-ethylaminocarbonyl substituted by carbocyclic aryl,    -   carbocyclic aryl,    -   heterocyclyl substituted by methyl,    -   heterocyclyl substituted by halogenated carbocyclic aryl,        (vi) heterocyclyl,        or heterocyclyl substituted by substituent(s) independently        selected from    -   halogen,    -   nitro,    -   C₁-C₄ alkyl,    -   C₁-C₄ alkyl substituted by substituent(s) independently selected        from        -   halogen,        -   methylthio substituted by halogenated carbocyclic aryl,        -   carbocyclic aryl,        -   halogenated carbocyclic aryl,        -   heterocyclyl,    -   methoxy,    -   carbocyclic aryloxy,    -   carbocyclic aryloxy substituted by methyl,    -   C₁-C₃ alkylthio,    -   propenylthio,    -   carbocyclic arylthio,    -   C₁-C₃ alkylsulfonyl,    -   carbocyclic arylsulfonyl substituted by C₁-C₄ alkyl,    -   carbocyclic aryl,    -   halogenated carbocyclic aryl,    -   carbocyclic aryl substituted by methyl,    -   carbocyclic aryl substituted by nitro,    -   heterocyclyl;

R₂ is methylamino or dimethylamino;

L is selected from Formula Va, VIIIa, or IXa;

wherein R₄ and R₅ are independently selected from H or C₁-C₃ alkyl;

Y is —C(O)—;

wherein carbocyclic aryl is phenyl, naphthyl, anthranyl, or biphenyl;

carbocyclyl is 1-oxo-indanyl, 9-oxo-fluorenyl, indenyl, anthraquinonyl,C-fluoren-9-ylidene, 1,2,3,4-tetrahydro-naphthyl, orbicyclo[2.2.1]hepteny;

heterocyclyl is 1,2,3-thiadiazolyl, 1,2,3-triazolyl,1,2-dihydro-3-oxo-pyrazolyl, 1,3-dioxo-isoindolyl, 1H-indolyl,1H-pyrrolyl, 1-oxo-3H-isobenzofuranyl, 2,3-dihydro-benzo[1,4]dioxinyl,2,4-dihydro-3-oxo-pyrazolyl, 2H-benzopyranyl, 2-oxo-benzopyranyl,3,4-dihydro-2H-benzo[b] [1,4]dioxepinyl, 4-oxo-3,4-dihydro-phthalazinyl,4-oxo-benzopyranyl, 9,10,10-trioxo-thioxanthenyl, 9H-xanthenyl,azetidinyl, benzimidazolyl, benzo[1,3]dioxolyl, benzo[2,1,3]oxadiazolyl,benzo[b]thienyl, furyl, imidazolyl, isoxazolyl, morpholino, morpholinyl,oxolanyl, piperidyl, piridyl, pyrazolyl, pyridyl, quinolyl, quinoxalyl,thiazolidyl, thiazolyl, thienyl, thiolanyl,2,3-dihydro-1-oxo-isoindolyl, 2,3-dihydro-benzofuryl,2-oxo-pyrrolidinyl, 4-oxo-1,5,6,7-tetrahydro-indolyl, cinnolyl,pyrimidyl, pyrrolidyl, tetrahydro-thienyl, benzofuranyl, orbenzothiazolyl;

halogen is fluoro, chloro, bromo, or iodo.

Other more preferred compounds of this invention are those compounds ofFormula I wherein,

Q is Formula II;

R₁ represents

(i) C₁-C₁₀ alkyl substituted by substituent(s) independently selectedfrom

-   -   oxo,    -   di-propylaminocarbonyl,    -   methoxy substituted by carbocyclic aryl,    -   methylcarbonyloxy,    -   carbocyclic aryloxy,    -   halogenated carbocyclic aryloxy,    -   carbocyclic aryloxy substituted by nitro,    -   heterocyclyloxy substituted by methyl,    -   substituted heterocyclyl-ethylideneaminooxy,    -   tert-butoxycarbonylamino,    -   carbocyclic arylcarbonylamino,    -   C₁-C₂ alkylthio,    -   C₁-C₂ alkylthio substituted by substituent(s) independently        selected from        -   halogenated carbocyclic aryl,        -   carbocyclic aryl substituted by methoxy,    -   carbocyclic arylthio,    -   hetrocyclylthio substituted by nitro,    -   hetrocyclylthio substituted by methyl,    -   C₅-C₆ cycloalkenyl,    -   carbocyclyl substituted by substituent(s) independently selected        from        -   halogen,        -   methyl,        -   methoxy,        -   ethenyl substituted by carbocyclic aryl substituted            methylsulfinyl,    -   carbocyclic aryl substituted by substituent(s) independently        selected from        -   halogen,        -   hydroxy,        -   nitro,        -   C₁-C₄ alkyl,        -   C₁-C₄ alkyl substituted by substituent(s) independently            selected from            -   oxo,            -   carbocyclic aryl,            -   heterocyclyl,        -   C₁-C₄ alkoxy,        -   halogenated C₁-C₄ alkoxy,        -   C₁-C₄ alkoxy substituted by carbocyclic aryl,        -   carbocyclic aryloxy,        -   halogenated mono-carbocyclic arylaminocarbonyl,        -   carbocyclic aryl,        -   heterocyclyl,    -   heterocyclyl substituted by substituent(s) independently        selected from        -   C₁-C₂ alkyl,        -   C₁-C₂ substituted by carbocyclic aryl,        -   methoxy,        -   methoxy substituted by carbocyclic aryl,        -   carbocyclic aryl,        -   halogenated carbocyclic aryl,            (ii) C₂-C₃ alkenyl substituted by substituent(s)            independently selected from    -   carbocyclic aryl,    -   halogenated carbocyclic aryl,    -   carbocyclic aryl substituted by nitro,        (iii) C₃-C₆ cycloalkyl substituted by substituent(s)        independently selected from    -   methyl substituted by oxo,    -   methyl substituted by carbocyclic aryl,    -   carbocyclic aryl,        (iv) carbocyclyl,        (v) carbocyclic aryl substituted by substituent(s) independently        selected from    -   halogen,    -   hydroxy,    -   cyano,    -   nitro,    -   C₁-C₉ alkyl,    -   C₁-C₉ alkyl substituted by substituent(s) independently selected        from        -   halogen,        -   oxo,        -   carbocyclic aryl,        -   carbocyclic aryl substituted by methyl,        -   carbocyclic aryloxy,    -   C₁-C₇ alkoxy,    -   halogenated C₁-C₇ alkoxy,    -   C₁-C₇ alkoxy substituted by carbocyclic aryl,    -   methylcarbonyloxy,    -   carbocyclic aryloxy,    -   carbocyclic aryloxy substituted by methoxy,    -   amino,    -   di-methylamino,    -   propargynylcarbonylamino substituted by carbocyclic aryl,    -   carbocyclic arylsulfonylamino substituted by methyl,    -   (carbocyclic aryl)NHC(O)NH substituted by halogenated methoxy,    -   halogenated methylthio,    -   carbocyclic arylthio substituted by cyano,    -   di-propylamino sulfonyl,    -   mono- or di-ethylaminocarbonyl substituted by carbocyclic aryl,    -   carbocyclic aryl,    -   heterocyclyl substituted by methyl,    -   heterocyclyl substituted by halogenated carbocyclic aryl,        (vi) or heterocyclyl substituted by substituent(s) independently        selected from    -   halogen,    -   nitro,    -   C₁-C₄ alkyl,    -   C₁-C₄ alkyl substituted by substituent(s) independently selected        from        -   halogen,        -   methylthio substituted by halogenated carbocyclic aryl,        -   carbocyclic aryl,        -   halogenated carbocyclic aryl,        -   heterocyclyl,    -   methoxy,    -   carbocyclic aryloxy,    -   carbocyclic aryloxy substituted by methyl,    -   C₁-C₃ alkylthio,    -   propenylthio,    -   carbocyclic arylthio,    -   C₁-C₃ alkylsulfonyl,    -   carbocyclic arylsulfonyl,    -   carbocyclic arylsulfonyl substituted by C₁-C₄ alkyl,    -   carbocyclic aryl,    -   halogenated carbocyclic aryl,    -   carbocyclic aryl substituted by methyl,    -   carbocyclic aryl substituted by nitro,    -   heterocyclyl;

R₂ is methylamino or dimethylamino;

L is selected from Formula XX-XXII;

Y is —C(O)—;

wherein carbocyclic aryl is phenyl, naphthyl, or biphenyl;

carbocyclyl is 1-oxo-indanyl, 9-oxo-fluorenyl, indenyl, anthraquinonyl,C-fluoren-9-ylidene, 1,2,3,4-tetrahydro-naphthyl, orbicyclo[2.2.1]hepteny;

heterocyclyl is 1,2,3-thiadiazolyl, 1,2,3-triazolyl,1,2-dihydro-3-oxo-pyrazolyl, 1H-indolyl, 1H-pyrrolyl,2,4-dihydro-3-oxo-pyrazolyl, 2H-benzopyranyl, 4-oxo-benzopyranyl,azetidinyl, benzo[b]thienyl, furyl, isoxazolyl, morpholinyl, piperidyl,piridyl, pyrazolyl, pyridyl, quinolyl, thiazolidyl, thiazolyl, thienyl,thiolanyl, 2,3-dihydro-1-oxo-isoindolyl, 2,3-dihydro-benzofuryl,2-oxo-benzopyranyl, 2-oxo-pyrrolidinyl,4-oxo-1,5,6,7-tetrahydro-indolyl, 9H-xanthenyl, cinnolyl, imidazolyl,morpholino, pyrimidyl, pyrrolidyl, tetrahydro-thienyl, benzofuranyl, orbenzothiazolyl;

halogen is fluoro, chloro, bromo, or iodo.

Further other more preferred compounds of this invention are thosecompounds of Formula I wherein,

Q is Formula II;

R₁ represents

(i) C₁-C₅ alkyl substituted by substituent(s) independently selectedfrom

-   -   oxo,    -   di-propylaminocarbonyl,    -   methoxy substituted by carbocyclic aryl,    -   methylcarbonyloxy,    -   carbocyclic aryloxy,    -   halogenated carbocyclic aryloxy,    -   carbocyclic aryloxy substituted by nitro,    -   heterocyclyloxy substituted by methyl,    -   substituted heterocyclyl-ethylideneaminooxy,    -   tert-butoxycarbonylamino,    -   carbocyclic arylcarbonylamino,    -   C₁-C₂ alkylthio,    -   C₁-C₂ alkylthio substituted by substituent(s) independently        selected from        -   halogenated carbocyclic aryl,        -   carbocyclic aryl substituted by methoxy,    -   carbocyclic arylthio,    -   hetrocyclylthio substituted by nitro,    -   hetrocyclylthio substituted by methyl,    -   cyclohexenyl,    -   carbocyclyl substituted by substituent(s) independently selected        from        -   halogen,        -   methyl,        -   methoxy,        -   ethenyl substituted by carbocyclic aryl substituted            methylsulfinyl,    -   carbocyclic aryl substituted by substituent(s) independently        selected from        -   halogen,        -   hydroxy,        -   nitro,        -   C₁-C₄ alkyl,        -   C₁-C₄ alkyl substituted by substituent(s) independently            selected from            -   oxo,            -   carbocyclic aryl,            -   heterocyclyl,        -   C₁-C₂ alkoxy,        -   halogenated C₁-C₂ alkoxy,        -   C₁-C₂ alkoxy substituted by carbocyclic aryl,        -   carbocyclic aryloxy,        -   halogenated mono-carbocyclic arylaminocarbonyl,        -   carbocyclic aryl,        -   heterocyclyl,    -   heterocyclyl substituted by substituent(s) independently        selected from        -   C₁-C₂ alkyl,        -   C₁-C₂ substituted by carbocyclic aryl,        -   methoxy,        -   methoxy substituted by carbocyclic aryl,        -   carbocyclic aryl,        -   halogenated carbocyclic aryl,            (ii) C₂-C₃ alkenyl substituted by substituent(s)            independently selected from    -   carbocyclic aryl,    -   halogenated carbocyclic aryl,    -   carbocyclic aryl substituted by nitro,        (iii) C₃-C₆ cycloalkyl substituted by substituent(s)        independently selected from    -   methyl substituted by oxo,    -   methyl substituted by carbocyclic aryl,    -   carbocyclic aryl,        (iv) carbocyclyl,        (v) carbocyclic aryl substituted by substituent(s) independently        selected from    -   halogen,    -   hydroxy,    -   cyano,    -   nitro,    -   C₁-C₄ alkyl,    -   C₁-C₂ alkyl substituted by substituent(s) independently selected        from        -   halogen,        -   oxo,        -   carbocyclic aryl,        -   carbocyclic aryl substituted by methyl,        -   carbocyclic aryloxy,    -   C₁-C₂ alkoxy,    -   halogenated C₁-C₂ alkoxy,    -   C₁-C₂ alkoxy substituted by carbocyclic aryl,    -   methylcarbonyloxy,    -   carbocyclic aryloxy,    -   carbocyclic aryloxy substituted by methoxy,    -   amino,    -   di-methylamino,    -   propargynylcarbonylamino substituted by carbocyclic aryl,    -   carbocyclic arylsulfonylamino substituted by methyl,

(carbocyclic aryl)NHC(O)NH substituted by halogenated methoxy,

-   -   halogenated methylthio,    -   carbocyclic arylthio substituted by cyano,    -   di-propylamino sulfonyl,    -   mono- or di-ethylaminocarbonyl substituted by carbocyclic aryl,    -   carbocyclic aryl,    -   heterocyclyl substituted by methyl,    -   heterocyclyl substituted by halogenated carbocyclic aryl,

(vi) or heterocyclyl substituted by substituent(s) independentlyselected from

-   -   halogen,    -   nitro,    -   C₁-C₄ alkyl,    -   C₁-C₄ alkyl substituted by substituent(s) independently selected        from        -   halogen,        -   methylthio substituted by halogenated carbocyclic aryl,        -   carbocyclic aryl,        -   halogenated carbocyclic aryl,        -   heterocyclyl,    -   methoxy,    -   carbocyclic aryloxy,    -   carbocyclic aryloxy substituted by methyl,    -   C₁-C₃ alkylthio,    -   propenylthio,    -   carbocyclic arylthio,    -   C₁-C₃ alkylsulfonyl,    -   carbocyclic arylsulfonyl,    -   carbocyclic arylsulfonyl substituted by methyl,    -   carbocyclic aryl,    -   halogenated carbocyclic aryl,    -   carbocyclic aryl substituted by methyl,    -   carbocyclic aryl substituted by nitro,    -   heterocyclyl;

R₂ is methylamino or dimethylamino;

L is selected from Formula XX-XXII;

Y is —C(O)—;

wherein carbocyclic aryl is phenyl, naphthyl, or biphenyl;

carbocyclyl is 1-oxo-indanyl, indenyl, 9-oxo-fluorenyl,1,2,3,4-tetrahydro-naphthyl, or bicyclo[2.2.1]hepteny;

heterocyclyl is 1H-indolyl, 2,4-dihydro-3-oxo-pyrazolyl, furyl,pyrazolyl, pyridyl, thienyl, 1,2,3-triazolyl, 1H-pyrrolyl,2,3-dihydro-1-oxo-isoindolyl, 2,3-dihydro-benzofuryl, 2H-benzopyranyl,2-oxo-benzopyranyl, 4-oxo-1,5,6,7-tetrahydro-indolyl, imidazolyl,isoxazolyl, morpholino, morpholinyl, pyrazolyl, pyrimidyl, quinolyl,thiazolyl, tetrahydro-thienyl, benzofuranyl, or benzothiazolyl;

halogen is fluoro, chloro, bromo, or iodo.

The following compounds are specially preffered;

Other more preferred compounds of this invention are those compounds ofFormula I wherein,

Q is Formula II;

R₁ represents

(i) C₁-C₁₀ alkyl,

C₁-C₁₀ alkyl substituted by substituent(s) independently selected from

-   -   C₅-C₆ cycloalkyl,    -   carbocyclic aryl,    -   heterocyclyl,        (ii) C₃-C₆ cycloalkyl,        (iii) carbocyclic aryl,        (iv) or heterocyclyl;

R₂ is methylamino or dimethylamino;

L is selected from Formula XX-XXII;

Y is —C(O)—;

wherein carbocyclic aryl is phenyl, naphthyl, anthranyl, or biphenyl;

heterocyclyl is 1,3-dioxo-isoindolyl, 1H-indolyl,1-oxo-3H-isobenzofuranyl, 2,3-dihydro-benzo[1,4]dioxinyl,3,4-dihydro-2H-benzo[b] [1,4]dioxepinyl, 4-oxo-3,4-dihydro-phthalazinyl,9,10,10-trioxo-thioxanthenyl, 9H-xanthenyl, benzimidazolyl,benzo[1,3]dioxolyl, benzo[2,1,3]oxadiazolyl, benzo[b]thienyl, furyl,imidazolyl, isoxazolyl, morpholino, oxolanyl, piperidyl, pyridyl,quinoxalyl, thienyl, quinolyl, or benzothiazolyl;

halogen is fluoro, chloro, bromo, or iodo.

Further other more preferred compounds of this invention are thosecompounds of Formula I wherein,

Q is Formula II;

R₁ represents

(i) C₁-C₄ alkyl,

C₁-C₄ alkyl substituted by substituent(s) independently selected from

-   -   cyclopentyl,    -   carbocyclic aryl,    -   heterocyclyl,        (ii) carbocyclic aryl,        (iii) or heterocyclyl;

R₂ is methylamino or dimethylamino;

L is selected from Formula XX-XXII;

Y is —C(O)—;

wherein carbocyclic aryl is phenyl, naphthyl, anthranyl, or biphenyl;

heterocyclyl is 9H-xanthenyl, benzo[1,3]dioxolyl,benzo[2,1,3]oxadiazolyl, benzo[b]thienyl, thienyl, 1H-indolyl,quinoxalyl, quinolyl, or benzothiazolyl;

halogen is fluoro, chloro, bromo, or iodo.

The following compounds are specially preffered;

Preferred compounds of this invention are those compounds of Formula Iwherein,

Q is Formula II;

R₁ represents

(i) C₁-C₁₀ alkyl,

C₁-C₁₀ alkyl substituted by substituent(s) independently selected from

-   -   halogen,    -   hydroxy,    -   oxo,    -   C₁-C₃ alkoxy,    -   C₁-C₃ alkoxy substituted by substituent(s) independently        selected from        -   carbocyclic aryl,        -   heterocyclyl,        -   heterocyclyl substituted by C₁-C₃ alkyl,    -   carbocyclic aryloxy,    -   carbocyclic aryloxy substituted by substituent(s) independently        selected from        -   halogen,        -   nitro,        -   carbocyclic aryl,        -   carbocyclic aryl substituted by C₁-C₃ alkoxy,        -   C₁-C₄ alkyl,        -   C₁-C₄ alkyl substituted by substituent(s) independently            selected from            -   mono- or di-C₁-C₃ alkylamino,            -   mono- or di-C₁-C₃ alkylamino substituted by carbocyclic                aryl,            -   mono- or di-C₁-C₃ alkylamino substituted by halogenated                carbocyclic aryl,    -   mono- or di-C₁-C₃ alkylamino,    -   mono- or di-C₁-C₃ alkylamino substituted by substituent(s)        independently selected from        -   cyano,        -   carbocyclic aryl,        -   heterocyclyl,    -   mono- or di-carbocyclic arylamino,    -   mono- or di-carbocyclic arylamino substituted by C₁-C₃ alkyl,    -   C₁-C₃ alkylcalbonylamino,    -   C₁-C₄ alkoxycalbonylamino,    -   carbocyclic arylsulfonylamino,    -   carbocyclic arylsulfonylamino substituted by substituent(s)        independently selected from        -   nitro,        -   C₁-C₃ alkyl,        -   mono- or di-C₁-C₃ alkylamino,    -   C₁-C₃ alkylthio,    -   C₁-C₃ alkylthio substituted by substituent(s) independently        selected from        -   mono- or di-carbocyclic arylamino,        -   halogenated mono- or di-carbocyclic arylamino,        -   carbocyclic aryl,        -   carbocyclic aryl substituted by substituent(s) independently            selected from            -   halogen,            -   C₁-C₃ alkoxy,    -   carbocyclic arylthio,    -   carbocyclic arylthio substituted by substituent(s) independently        selected from        -   halogen,        -   C₁-C₃ alkyl,    -   carbocyclic arylsulfonyl,    -   halogenated carbocyclic arylsulfonyl,    -   heterocyclylthio,    -   C₃-C₆ cycloalkyl,    -   C₃-C₆ cycloalkyl substituted by C₁-C₃ alkyl,    -   carbocyclyl,    -   carbocyclyl substituted by substituent(s) independently selected        from        -   halogen,        -   C₁-C₃ alkyl,        -   C₂-C₃ alkenyl,        -   C₂-C₃ alkenyl substituted by carbocyclic aryl,        -   C₂-C₃ alkenyl substituted by carbocyclic aryl substituted            C₁-C₃ alkylsulfinyl,    -   carbocyclic aryl,    -   carbocyclic aryl substituted by substituent(s) independently        selected from        -   halogen,        -   hydroxy,        -   nitro,        -   C₁-C₄ alkyl,        -   C₁-C₄ alkyl substituted by substituent(s) independently            selected from            -   halogen,            -   hydroxy,            -   carbocyclic aryl,            -   mono- or di-carbocyclic arylamino,            -   mono- or di-carbocyclic arylamino substituted by                substituent(s) independently selected from                -   halogen,                -   nitro,                -   C₁-C₃ alkyl,                -   C₁-C₃ alkoxy,                -   halogenated C₁-C₃ alkoxy,        -   C₁-C₃ alkoxy,        -   C₁-C₃ alkoxy substituted by substituent(s) independently            selected from            -   halogen,            -   carbocyclic aryl,        -   carbocyclic aryloxy,        -   C₁-C₃ alkoxycarbonyl,        -   mono- or di-C₁-C₃ alkylamino,        -   C₁-C₃ alkylthio,        -   halogenated C₁-C₃ alkylthio,        -   C₁-C₃ alkylsulfonyl,        -   C₃-C₆ cycloalkyl,        -   carbocyclic aryl,        -   heterocyclyl,    -   heterocyclyl,    -   heterocyclyl substituted by substituent(s) independently        selected from        -   C₁-C₃ alkyl,        -   C₁-C₃ alkoxy,        -   C₁-C₃ alkoxy substituted by carbocyclic aryl,        -   carbocyclic aryl,        -   halogenated carbocyclic aryl,            (ii) C₂-C₈ alkenyl,            C₂-C₈ alkenyl substituted by substituent(s) independently            selected from    -   halogen,    -   C₁-C₃ alkoxy,    -   C₁-C₃ alkoxy substituted by carbocyclic aryl,    -   carbocyclic aryl,    -   carbocyclic aryl substituted by substituent(s) independently        selected from halogen,        -   hydroxy,        -   C₁-C₃ alkoxy,        -   halogenated C₁-C₃ alkoxy,    -   heterocyclyl,    -   heterocyclyl substituted by nitro,        (iii) C₂-C₄ alkynyl,        C₂-C₄ alkynyl substituted by carbocyclic aryl,        (iv) C₃-C₆ cycloalkyl,        C₃-C₆ cycloalkyl substituted by substituent(s) independently        selected from    -   C₁-C₃ alkyl,    -   C₁-C₃ alkyl substituted by substituent(s) independently selected        from        -   hydroxy,        -   oxo,        -   carbocyclic aryl,    -   mono- or di-C₁-C₃ akylamino,    -   mono- or di-C₁-C₃ alkylamino substituted by carbocyclic aryl,    -   carbocyclic aryl,        (v) C₃-C₆ cycloalkeyl,        C₃-C₆ cycloalkeyl substituted by C₁-C₃ alkyl,        (vi) carbocyclyl,        carbocyclyl substituted by substituent(s) independently selected        from    -   hydroxy,    -   nitro,        (vii) carbocyclic aryl,        carbocyclic aryl substituted by substituent(s) independently        selected from    -   halogen,    -   hydroxy,    -   cyano,    -   nitro,    -   C₁-C₉ alkyl,    -   C₁-C₉ alkyl substituted by substituent(s) independently selected        from        -   halogen,        -   hydroxy,        -   oxo,        -   C₁-C₃ alkoxy,        -   carbocyclic aryloxy,        -   mono- or di-C₁-C₃ alkylamino-N-oxy,        -   mono- or di-C₁-C₃ alkylamino,        -   mono- or di-C₁-C₃ alkylamino substituted by carbocyclic            aryl,        -   mono- or di-carbocyclic arylamino,        -   mono- or di-carbocyclic arylamino substituted by C₁-C₃            alkoxy,        -   carbocyclic aryl,        -   halogenated carbocyclic aryl,        -   heterocyclyl,        -   heterocyclyl substituted by C₁-C₃ alkyl,    -   C₂-C₃ alkenyl,    -   C₂-C₃ alkenyl substituted by carbocyclic aryl,    -   C₁-C₉ alkoxy,    -   C₁-C₉ alkoxy substituted by substituent(s) independently        selected from        -   hydroxy,        -   halogen,        -   carboxy,        -   mono- or di-C₁-C₃ alkylamino,        -   carbocyclic aryl,        -   halogenated carbocyclic aryl,        -   heterocyclyl,        -   heterocyclyl substituted by substituent(s) independently            selected from            -   heterocyclyl,            -   heterocyclyl substituted by substituent(s) independently                selected from                -   halogen,                -   C₁-C₃ alkyl,                -   halogenated C₁-C₃ alkyl,    -   C₂-C₃ alkenyloxy,    -   C₁-C₃ alkylcarbonyloxy,    -   carbocyclic aryloxy,    -   carbocyclic aryloxy substituted by substituent(s) independently        selected from        -   halogen,        -   C₁-C₄ alkyl,        -   halogenated C₁-C₄ alkyl,        -   C₁-C₃ alkoxy,    -   heterocyclyloxy,    -   heterocyclyloxy substituted by substituent(s) independently        selected from        -   halogen,        -   C₁-C₃ alkyl,        -   halogenated C₁-C₃ alkyl,    -   (carbocyclic aryl)S(O)₂O,    -   carboxy,    -   C₁-C₃ alkoxycarbonyl,    -   mono- or di-C₁-C₃ alkylaminocarbonyl,    -   mono- or di-C₁-C₃ alkylaminocarbonyl substituted by carbocyclic        aryl,    -   amino,    -   mono- or di-C₁-C₄ alkylamino,    -   mono- or di-C₁-C₄ alkylamino substituted by cyano,    -   mono- or di-carbocyclic arylamino,    -   C₁-C₃ alkylcarbonylamino,    -   carbocyclic arylsulfonylamino,    -   carbocyclic arylsulfonylamino substituted by C₁-C₃ alkyl,    -   (carbocyclic aryl)NHC(O)NH,    -   (carbocyclic aryl)NHC(O)NH substituted by C₁-C₃ alkoxy,    -   (carbocyclic aryl)NHC(O)NH substituted by haloganated C₁-C₃        alkoxy,    -   C₁-C₃ alkylthio,    -   halogenated C₁-C₃ alkylthio,    -   carbocyclic arylthio,    -   halogenated carbocyclic arylthio,    -   carbocyclic arylthio substituted by C₁-C₃ alkyl,    -   heterocyclylthio,    -   C₁-C₃ alkylsulfonyl,    -   mono- or di-C₁-C₃ alkylaminosulfonyl,    -   carbocyclic aryl,    -   carbocyclic aryl substituted by substituent(s) independently        selected from        -   C₁-C₇ alkyl,        -   halogenated C₁-C₇ alkyl,    -   heterocyclyl,    -   heterocyclyl substituted by substituent(s) independently        selected from        -   C₁-C₃ alkyl,        -   carbocyclic aryl,        -   halogenated carbocyclic aryl,            (viii) heterocyclyl,            or heterocyclyl substituted by substituent(s) independently            selected from    -   halogen,    -   hydroxy,    -   cyano,    -   nitro,    -   C₁-C₄ alkyl,    -   C₁-C₄ alkyl substituted by substituent(s) independently selected        from        -   halogen,        -   hydroxy,        -   oxo,        -   C₁-C₃ alkylcarbonyloxy,        -   C₁-C₃ alkoxycarbonyl,        -   C₁-C₃ alkylthio,        -   C₁-C₃ alkylthio substituted by carbocyclic aryl,        -   C₁-C₃ alkylthio substituted by halogenated carbocyclic aryl,        -   carbocyclic aryl,        -   carbocyclic aryl substituted by substituent(s) independently            selected from            -   halogen,            -   nitro,        -   heterocyclyl,    -   C₁-C₃ alkoxy,    -   C₁-C₃ alkoxy substituted by carbocyclic aryl,    -   carbocyclic aryloxy,    -   carbocyclic aryloxy substituted by C₁-C₃ alkyl,    -   mono- or di-C₁-C₃ alkylamino,    -   C₁-C₄ alkylcarbonylamino,    -   C₁-C₃ alkylthio,    -   carbocyclic arylthio,    -   halogenated carbocyclic arylthio,    -   carbocyclic arylthio substituted by C₁-C₃ alkoxycarbonyl,    -   heterocyclylthio,    -   heterocyclylthio substituted by C₁-C₃ alkyl,    -   C₁-C₃ alkylsulfonyl,    -   carbocyclic arylsulfonyl,    -   carbocyclic arylsulfonyl substituted by C₁-C₄ alkyl,    -   C₁-C₃ alkoxycarbonyl,    -   carbocyclic aryl,    -   carbocyclic aryl substituted by substituent(s) independently        selected from        -   halogen,        -   nitro,        -   C₁-C₃ alkyl,        -   halogenated C₁-C₃ alkyl,        -   C₁-C₃ alkoxy,        -   halogenated C₁-C₃ alkoxy,    -   heterocyclyl,    -   heterocyclyl substituted by substituent(s) independently        selected from        -   C₁-C₃ alkyl,        -   halogenated C₁-C₃ alkyl,        -   C₁-C₃ alkoxy,        -   C₁-C₃ alkoxycarbonyl;

R₂ is —NHNH₂, —NHNHBoc, —N(R_(2a))(R_(2b)), morpholino,4-acetyl-piperazyl, or 4-phenyl-piperazyl;

wherein R_(2a) is H or C₁-C₃ alkyl;

R_(2b) is C₁-C₄ alkyl, C₁-C₄ alkyl substituted by substituent(s)independently selected from

-   -   hydroxy,    -   C₁-C₃ alkoxy,    -   amino,    -   —NHBoc,    -   C₃-C₆ cycloalkyl,    -   carbocyclic aryl,    -   carbocyclic aryl substituted by substituent(s) independently        selected from        -   halogen,        -   C₁-C₃ alkyl,        -   C₁-C₃ alkoxy,        -   —SO₂NH₂,    -   heterocyclyl,        C₃-C₆ cycloalkyl, carbocyclic aryl, carbocyclic aryl substituted        by substituent(s) independently selected from    -   halogen,    -   C₁-C₃ alkyl,    -   C₁-C₃ alkoxy,        or a group of Formula IV;

wherein Boc is carbamic acid tert-butyl ester and R₃ is C₁-C₃ alkyl orC₁-C₃ alkyl substituted by substituent(s) independently selected from

-   -   carbocyclic aryl,    -   halogenated carbocyclic aryl,    -   carbocyclic aryl substituted by C₁-C₃ alkoxy;

L is selected from Formula V-XIX;

wherein R₄ is H or C₁-C₃ alkyl;

R₅ is H, C₁-C₃ alkyl, or C₁-C₃ alkyl substituted by a substitutedcarbocyclic aryl;

Y is —(CH₂)_(m), m is 0 or 1;

wherein carbocyclic aryl is phenyl, naphthyl, phenanthryl, or biphenyl;

carbocyclyl is 9H-fluorenyl, 9-oxo-fluorenyl, acenaphthyl,anthraquinonyl, indanyl, or indenyl;

heterocyclyl is 1,2,3-thiadiazolyl, 1,2,3-triazolyl,1,2-dihydro-3-oxo-pyrazolyl, 1,3,4-thiadiazolyl, 1,3-dioxo-isoindolyl,1,3-dioxolanyl, 1H-indolyl, 1H-pyrrolo[2,3-c]pyridyl, 1H-pyrrolyl,2,2′,5′,2″-terthiophenyl, 2,2′-bithiophenyl,2,3-dihydro-1-oxo-isoindolyl, 2,3-dihydro-benzo[1,4]dioxinyl,2,3-dihydro-benzofuryl, 2,4-dihydro-3-oxo-pyrazolyl, 2H-benzopyranyl,2-oxo-pyrrolidinyl, 3,4-dihydro-2H-benzo[1,4]oxazinyl,3,4-dihydro-2H-benzo[b][1,4]dioxepinyl, 4H-benzo[1,3]dioxinyl,4H-benzopyranyl, 4-oxo-1,5,6,7-tetrahydro-indolyl, 4-oxo-benzopyranyl,9H-carbazolyl, 9H-xanthenyl, azetidinyl, benzimidazolyl,benzo[1,3]dioxolyl, benzo[b]thienyl, benzofuryl, benzothiazolyl, furyl,imidazo[2,1-b]thiazolyl, imidazolyl, isoxazolyl, morpholino,morpholinyl, oxolanyl, piperazyl, piperidyl, pyrazolo[5,1-b]thiazolyl,pyrazolyl, pyridyl, pyrimidyl, pyrrolidyl, quinolyl, quinoxalyl,thiazolidyl, thiazolyl, thienyl, or thiolanyl;

halogen is fluoro, chloro, bromo, or iodo.

Other preferred compounds of this invention are those compounds ofFormula I wherein,

Q is Formula II;

R₁ represents

(i) C₁-C₁₀ alkyl substituted by substituent(s) independently selectedfrom

-   -   methoxy,    -   methoxy substituted by carbocyclic aryl,    -   carbocyclic aryloxy,    -   halogenated carbocyclic aryloxy,    -   mono-C₁-C₂ aklylamino substituted by cyano,    -   mono- or di-C₁-C₂ alkylamino substituted by carbocyclic aryl,    -   mono-carbocyclic arylamino,    -   mono-carbocyclic arylamino substituted by methyl,    -   carbocyclic arylsulfonylamino substituted by methyl,    -   carbocyclic aryl,    -   carbocyclic aryl substituted by substituent(s) independently        selected from        -   halogen,        -   nitro,        -   C₁-C₄ alkyl,        -   C₁-C₄ alkyl substituted by carbocyclic aryl,        -   C₁-C₄ alkyl substituted by hydroxy,        -   C₁-C₂ alkoxy,        -   halogenated C₁-C₂ alkoxy,    -   heterocyclyl substituted by carbocyclic aryl,        (ii) C₂-C₈ alkenyl substituted by substituent(s) independently        selected from    -   methoxy substituted by carbocyclic aryl,    -   carbocyclic aryl,    -   carbocyclic aryl substituted by methoxy,        (iii) C₂-C₄ alkynyl substituted by carbocyclic aryl,        (iv) cyclohexyl substituted by carbocyclic arylmethyl,        (v) carbocyclyl,        (vi) carbocyclic aryl,        carbocyclic aryl substituted by substituent(s) independently        selected from    -   halogen,    -   hydroxy,    -   cyano,    -   amino,    -   C₁-C₉ alkyl,    -   halogenated C₁-C₉ alkyl,    -   C₁-C₉ alkoxy,    -   C₁-C₉ alkoxy substituted by substituent(s) independently        selected from        -   halogen,        -   halogenated carbocyclic aryl,    -   propenyloxy,    -   methylamino,    -   di-C₁-C₂ alkylamino,    -   di-C₁-C₂ alkylamino substituted by cyano,    -   methylthio,    -   halogenated methylthio,        (vii) heterocyclyl,        or heterocyclyl substituted by substituent(s) independently        selected from    -   halogen,    -   C₁-C₄ alkyl,    -   C₁-C₄ alkyl substituted by hydroxy,    -   C₁-C₄ alkyl substituted by carbocyclic aryl,    -   methoxy,    -   C₁-C₂ alkoxycarbonyl,    -   carbocyclic arylthio substituted by methoxycarbonyl,    -   carbocyclic aryl,    -   carbocyclic aryl substituted by substituent(s) independently        selected from        -   halogen,        -   halogenated methyl,    -   heterocyclyl;

R₂ is methylamino or dimethylamino;

L is selected from Formula Va, VIIIa, or IXa;

wherein R₄ and R₅ are independently selected from H or C₁-C₃ alkyl;

Y is —(CH₂)_(m), m is 0 or 1;

wherein carbocyclic aryl is phenyl, naphthyl, phenanthryl, or biphenyl;

carbocyclyl is 9H-fluorenyl, acenaphthyl, or anthraquinonyl;

heterocyclyl is 1,2,3-thiadiazolyl, 1,2,3-triazolyl,1,2-dihydro-3-oxo-pyrazolyl, 1,3-dioxolanyl, 1H-indolyl, 1H-pyrrolyl,2,2′,5′,2″-terthiophenyl, 2,2′-bithiophenyl,2,3-dihydro-benzo[1,4]dioxinyl, 3,4-dihydro-2H-benzo[1,4]oxazinyl,4-oxo-benzopyranyl, 9H-carbazolyl, 9H-xanthenyl, benzimidazolyl,benzo[1,3]dioxolyl, benzo[b]thienyl, benzofuryl, benzothiazolyl, furyl,imidazolyl, isoxazolyl, oxolanyl, pyrazolo[5,1-b]thiazolyl, pyrazolyl,pyridyl, pyrimidyl, quinolyl, quinoxalyl, thiazolidyl, thiazolyl,thienyl, 2H-benzopyranyl, 4H-benzo[1,3]dioxinyl, azetidinyl,imidazo[2,1-b]thiazolyl, morpholinyl, or 2,3-dihydro-benzofuryl;

halogen is fluoro, chloro, bromo, or iodo.

Other more preferred compounds of this invention are those compounds ofFormula I wherein,

Q is Formula II;

R₁ represents

(i) C₁-C₇ alkyl substituted by substituent(s) independently selectedfrom

-   -   methoxy,    -   methoxy substituted by carbocyclic aryl,    -   carbocyclic aryloxy,    -   halogenated carbocyclic aryloxy,    -   mono-ethylamino substituted by cyano,    -   di-methylamino substituted by carbocyclic aryl,    -   mono-carbocyclic arylamino,    -   mono-carbocyclic arylamino substituted by methyl,    -   carbocyclic arylsulfonylamino substituted by methyl,    -   carbocyclic aryl,    -   carbocyclic aryl substituted by substituent(s) independently        selected from        -   halogen,        -   nitro,        -   C₁-C₄ alkyl,        -   C₁-C₄ alkyl substituted by carbocyclic aryl,        -   C₁-C₄ alkyl substituted by hydroxy,        -   metoxy,        -   halogenated methoxy,    -   heterocyclyl substituted by carbocyclic aryl,        (ii) C₂-C₇ alkenyl substituted by substituent(s) independently        selected from    -   methoxy substituted by carbocyclic aryl,    -   carbocyclic aryl,    -   carbocyclic aryl substituted by methoxy,        (iii) butynyl substituted by carbocyclic aryl,        (iv) cyclohexyl substituted by carbocyclic arylmethyl,        (v) carbocyclyl,        (vi) carbocyclic aryl,        carbocyclic aryl substituted by substituent(s) independently        selected from    -   halogen,    -   hydroxy,    -   cyano,    -   amino,    -   C₁-C₂ alkyl,    -   halogenated methyl,    -   C₁-C₃ alkoxy,    -   C₁-C₃ alkoxy substituted by substituent(s) independently        selected from        -   halogen,        -   halogenated carbocyclic aryl,    -   propenyloxy,    -   di-C₁-C₂ alkylamino,    -   di-C₁-C₂ alkylamino substituted by cyano,    -   methylthio,    -   halogenated methylthio,        (vii) heterocyclyl,        or heterocyclyl substituted by substituent(s) independently        selected from    -   halogen,    -   C₁-C₃ alkyl,    -   C₁-C₃ alkyl substituted by hydroxy,    -   C₁-C₃ alkyl substituted by carbocyclic aryl,    -   methoxy,    -   ethoxycarbonyl,    -   carbocyclic arylthio substituted by methoxycarbonyl,    -   carbocyclic aryl,    -   carbocyclic aryl substituted by substituent(s) independently        selected from        -   halogen,        -   halogenated methyl,    -   heterocyclyl;

R₂ is methylamino or dimethylamino;

L is selected from Formula XX-XXII;

Y is —(CH₂)_(m), m is 0 or 1;

wherein carbocyclic aryl is phenyl, naphthyl, or biphenyl;

carbocyclyl is acenaphthyl;

heterocyclyl is 1H-indolyl, 1H-pyrrolyl, 2,3-dihydro-benzo[1,4]dioxinyl,9H-carbazolyl, benzo[1,3]dioxolyl, furyl, pyrazolyl, thienyl,4-oxo-benzopyranyl, azetidinyl, imidazo[2,1-b]thiazolyl, pyridyl,imidazolyl, 2,3-dihydro-benzofuryl, or benzo[b]thienyl;

halogen is fluoro, chloro, bromo, or iodo.

The following compounds are specially preffered;

Preferred compounds of this invention are those compounds of Formula Iwherein,

Q is Formula II;

R₁ represents

(i) C₁-C₁₆ alkyl,

C₁-C₁₆ alkyl substituted by substituent(s) independently selected from

-   -   halogen,    -   carbocyclyl,    -   carbocyclic aryl,    -   carbocyclic aryl substituted by substituent(s) independently        selected from        -   halogen,        -   nitro,        -   C₁-C₃ alkyl,        -   halogenated C₁-C₃ alkyl,            (ii) C₂-C₃ alkenyl,            C₂-C₃ alkenyl substituted by carbocyclic aryl,            (iii) carbocyclic aryl,            carbocyclic aryl substituted by substituent(s) independently            selected from    -   halogen,    -   cyano,    -   nitro,    -   C₁-C₅ alkyl,    -   C₁-C₅ alkyl substituted by substituent(s) independently selected        from        -   halogen,        -   oxo,    -   C₂-C₃ alkenyl,    -   C₁-C₄ alkoxy,    -   C₁-C₄ alkoxy substituted by substituent(s) independently        selected from        -   halogen,        -   heterocyclyl,        -   halogenated heterocyclyl,    -   carbocyclic aryloxy,    -   carbocyclic aryloxy substituted by substituent(s) independently        selected from        -   halogen,        -   nitro,    -   heterocyclyloxy,    -   heterocyclyloxy substituted by substituent(s) independently        selected from        -   halogen,        -   C₁-C₃ alkyl,        -   halogenated C₁-C₃ alkyl,    -   C₁-C₃ alkoxycarbonyl,    -   mono- or di-C₁-C₄ alkylamino,    -   C₁-C₃ alkylcarbonylamino,    -   carbocyclic aryl diazo,    -   carbocyclic aryl diazo substituted by mono- or di-C₁-C₃        alkylamino,    -   C₁-C₃ alkylsulfonyl,    -   carbocyclic aryl,        (iv) heterocyclyl,        or heterocyclyl substituted by substituent(s) independently        selected from    -   halogen,    -   C₁-C₃ alkyl,    -   C₁-C₃ alkyl substituted by substituent(s) independently selected        from        -   halogen,        -   oxo,        -   carbocyclic arylcarbonylamino,        -   halogenated carbocyclic arylcarbonylamino,        -   heterocyclyl,        -   heterocyclyl substituted by substituent(s) independently            selected from            -   halogen,            -   C₁-C₃ alkyl,            -   halogenated C₁-C₃ alkyl,    -   C₁-C₃ alkoxy,    -   C₁-C₃ alkylcarbonylamino,    -   carbocyclic arylsulfonyl,    -   C₁-C₃ alkoxycarbonyl,    -   carbocyclic aryl,    -   halogenated carbocyclic aryl,    -   heterocyclyl,    -   heterocyclyl substituted by substituent(s) independently        selected from        -   halogen,        -   C₁-C₃ alkyl,        -   halogenated C₁-C₃ alkyl;            -   R₂ is —NHNH₂, —NHNHBoc, —N(R_(2a))(R_(2b)); morpholino,                4-acetyl-piperazyl, or 4-phenyl-piperazyl;                wherein R_(2a) is H or C₁-C₃ alkyl;                R_(2b) is C₁-C₄ alkyl, C₁-C₄ alkyl substituted by                substituent(s) independently selected from    -   hydroxy,    -   C₁-C₃ alkoxy,    -   amino,    -   —NHBoc,    -   C₃-C₆ cycloalkyl,    -   carbocyclic aryl,    -   carbocyclic aryl substituted by substituent(s) independently        selected from        -   halogen,        -   C₁-C₃ alkyl,        -   C₁-C₃ alkoxy,        -   —SO₂NH₂,    -   heterocyclyl,        C₃-C₆ cycloalkyl, carbocyclic aryl, carbocyclic aryl substituted        by substituent(s) independently selected from    -   halogen,    -   C₁-C₃ alkyl,    -   C₁-C₃ alkoxy,        or a group of Formula IV;

wherein Boc is carbamic acid tert-butyl ester and R₃ is C₁-C₃ alkyl orC₁-C₃ alkyl substituted by substituent(s) independently selected from

-   -   carbocyclic aryl,    -   halogenated carbocyclic aryl,    -   carbocyclic aryl substituted by C₁-C₃ alkoxy;

L is selected from Formula V-XIX;

wherein R₄ is H or C₁-C₃ alkyl;

R₅ is H, C₁-C₃ alkyl, or C₁-C₃ alkyl substituted by a substitutedcarbocyclic aryl;

Y is —S(O)₂—;

wherein carbocyclic aryl is phenyl, naphthyl, or biphenyl;

carbocyclyl is 7,7-dimethyl-2-oxo-bicyclo[2.2.1]heptyl;

-   -   heterocyclyl is 1,2,3,4-tetrahydro-isoquinolyl,        1,2,3-thiadiazolyl, 1H-pyrrolyl, benzo[2,1,3]oxadiazolyl,        benzo[b]thienyl, furyl, imidazolyl, isoxazolyl, pyrazolyl,        pyridyl, quinolyl, thiazolyl, or thienyl;

halogen is fluoro, chloro, bromo, or iodo.

The following compounds are specially preffered;

Preferred compounds of this invention are those compounds of Formula Iwherein,

Q is Fomura II;

R₁ is selected from H, —CO₂ ^(t)Bu, or —CO₂Bn (Bn is a benzyl group);

R₂ is methylamino or dimethylamino;

L is selected from Formula XX-XXII;

Y is a single bond;

or a salt thereof.

One embodiment of the invention includes any compound of the inventionwhich selectively binds an MCH receptor, such selective binding ispreferably demonstrated by a Ki for one or more other GPCR(s),preferably NPY, being at least 10-fold greater than the Ki for anyparticular MCH receptor, preferable MCHR1.

As used herein, the term “alkyl” is intended to denote hydrocarboncompounds including straight chain and branched chain, including forexample but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl,sec-butyl, tert-butyl, n-pentyl, isopentyl, tert-pentyl, n-hexyl, andthe like.

The term “alkoxy” is intended to denote substituents of the formula

—O-alkyl.

At various places in the present specification substituents of compoundsof the invention are disclosed in groups. It is specifically intendedthat the invention include each and every individual subcombination ofthe members of such groups.

G-protein coupled receptors (GPCRs) represent a major class of cellsurface receptors with which many neurotransmitters interact to mediatetheir effects. GPCRs are predicted to have seven membrane-spanningdomains and are coupled to their effectors via G-proteins linkingreceptor activation with intracellular biochemical sequelae such asstimulation of adenylyl cyclase. Melanin Concentrating Hormone (MCH), acyclic peptide, has been identified as the endogenous ligand of theorphan G-protein coupled receptor SLC-1. See, for example, Shimomura etal., Biochem. Biophys. Res. Commun. 261, 622-26 (1999). Studies haveindicated that MCH acts as a neurotransmitter/modulator/regulator toalter a number of behavioral responses.

Mammalian MCH (19 amino acids) is highly conserved between rat, mouse,and human, exhibiting 100% amino acid identity, but its physiologicalroles are less clear. MCH has been reported to participate in a varietyof processes including feeding, water balance, energy metabolism,general arousal/attention state, memory and cognitive functions, andpsychiatric disorders. For reviews, see 1. Baker, Int. Rev. Cytol.126:1-47 (1991); 2. Baker, TEM 5:120-126 (1994); 3. Nahon, Critical Rev.in Neurobiol 221:221-262, (1994); 4. Knigge et al., Peptides18(7):1095-1097, (1996). The role of MCH in feeding or body weightregulation is supported by Qu et al., Nature 380:243-247, (1996),demonstrating that MCH is over expressed in the hypothalamus of ob/obmice compared with ob/+mice, and that fasting further increased MCH mRNAin both obese and normal mice during fasting. MCH also stimulatedfeeding in normal rats when injected into the lateral ventricles asreported by Rossi et al., Endocrinology 138:351-355, (1997). MCH alsohas been reported to functionally antagonize the behavioral effects ofα-MSH; see: Miller et al., Peptides 14:1-10, (1993); Gonzalez et al,Peptides 17:171-177, (1996); and Sanchez et al., Peptides 18:3933-396,(1997). In addition, stress has been shown to increase POMC mRNA levelswhile decreasing the MCH precursor preproMCH (ppMCH) mRNA levels; Presseet al., Endocrinology 131:1241-1250, (1992). Thus MCH may serve as anintegrative neuropeptide involved in the reaction to stress, as well asin the regulation of feeding and sexual activity; Baker, Int. Rev.Cytol. 126:1-47, (1991); Knigge et al., Peptides 17:1063-1073, (1996).

The localization and biological activities of MCH peptide suggest thatthe modulation of MCH receptor activity may be useful in a number oftherapeutic applications. MCH is expressed in the lateral hypothalamus,a brain area implicated in the regulation of thirst and hunger: Grillonet al., Neuropeptides 31:131-136, (1997); recently orexins A and B,which are potent orexigenic agents, have been shown to have very similarlocalization to MCH in the lateral hypothalamus; Sakurai et al., Cell92:573-585 (1998). MCH mRNA levels in this brain region are increased inrats after 24 hours of food-deprivation; Herve and Fellmann,Neurpeptides 31:237-242 (1997); after insulin injection, a significantincrease in the abundance and staining intensity of MCH immunoreactiveperikarya and fibres was observed concurrent with a significant increasein the level of MCH mRNA; Bahjaoui-Bouhaddi et al., Neuropeptides24:251-258, (1994). Consistent with the ability of MCH to stimulatefeeding in rats; Rossi et al., Endocrinology 138:351-355, (1997); is theobservation that MCH mRNA levels are upregulated in the hypothalami ofobese ob/ob mice; Qu et al., Nature 380:243-247, (1996); and decreasedin the hypothalami of rats treated with leptin, whose food intake andbody weight gains are also decreased; Sahu, Endocrinology 139:795-798,(1998). MCH appears to act as a functional antagonist of themelanocortin system in its effects on food intake and on hormonesecretion within the HPA (hypothalamopituitary/adrenal axis); Ludwig etal., Am. J. Physiol. Endocrinol. Metab. 274:E627-E633, (1998). Togetherthese data suggest a role for endogenous MCH in the regulation of energybalance and response to stress, and provide a rationale for thedevelopment of specific compounds acting at MCH receptors for use in thetreatment of obesity and stress-related disorders.

Accordingly, a MCH receptor antagonist is desirable for the prophylaxisor treatment of obesity or obesity related disorders. An obesity relateddisorder is a disorder that has been directly or indirectly associatedto obesity, such as, type II diabetes, syndrome X, impaired glucosetolerance, dyslipidaemia, hypertension, coronary heart disease and othercardiovascular disorders including atherosclerosis, insulin resistanceassociated with obesity and psoriasis, for treating diabeticcomplications and other diseases such as polycystic ovarian syndrome(PCOS), certain renal diseases including diabetic nephropathy,glomerulonephritis, glomerular sclerosis, nephrotic syndrome,hypertensive nephrosclerosis, end-stage renal diseases andmicroalbuminuria as well as certain eating disorders.

In species studied to date, a major portion of the neurons of the MCHcell group occupies a rather constant location in those areas of thelateral hypothalamus and subthalamus where they lie and may be a part ofsome of the so-called “extrapyramidal” motor circuits. These involvesubstantial striato- and pallidofugal pathways involving the thalamusand cerebral cortex, hypothalamic areas, and reciprocal connections tosubthalamic nucleus, substantia nigra, and mid-brain centers;Bittencourt et al., J. Comp. Neurol. 319:218-245, (1992). In theirlocation, the MCH cell group may offer a bridge or mechanism forexpressing hypothalamic visceral activity with appropriate andcoordinated motor activity. Clinically it may be of some value toconsider the involvement of this MCH system in movement disorders, suchas Parkinson's disease and Huntingdon's Chorea in which extrapyramidalcircuits are known to be involved.

Human genetic linkage studies have located authentic hMCH loci onchromosome 12 (12q23-24) and the variant hMCH loci on chromosome 5(5q12-13) (Pedeutour et al., 1994). Locus 12q23-24 coincides with alocus to which autosomal dominant cerebellar ataxia type II (SCA2) hasbeen mapped; Auburger et al., Cytogenet. Cell. Genet. 61:252-256,(1992); Twells et al., Cytogenet. Cell. Genet. 61:262-265, (1992). Thisdisease comprises neurodegenerative disorders, including anolivopontocerebellar atrophy. Furthermore, the gene for Darier'sdisease, has been mapped to locus 12q23-24; Craddock et al., Hum. Mol.Genet. 2:1941-1943, (1993). Dariers' disease is characterized byabnormalities I keratinocyte adhesion and mental illnesses in somefamilies. In view of the functional and neuroanatomical patterns of theMCH neural system in the rat and human brains, the MCH gene mayrepresent a good candidate for SCA2 or Darier's disease. Interestingly,diseases with high social impact have been mapped to this locus. Indeed,the gene responsible for chronic or acute forms of spinal muscularatrophies has been assigned to chromosome 5q12-13 using genetic linkageanalysis; Melki et al., Nature (London) 344:767-768, (1990); Westbrooket al., Cytogenet. Cell. Genet. 61:225-231, (1992). Furthermore,independent lines of evidence support the assignment of a majorschizophrenia locus to chromosome 5q11.2-13.3; Sherrington et al.,Nature (London) 336:164-167, (1988); Bassett et al., Lancet 1:799-801,(1988); Gilliam et al., Genomics 5:940-944, (1989). The above studiessuggest that MCH may play a role in neurodegenerative diseases anddisorders of emotion.

Additional therapeutic applications for MCH-related compounds aresuggested by the observed effects of MCH in other biological systems.For example, MCH may regulate reproductive functions in male and femalerats. MCH transcripts and MCH peptide were found within germ cells intestes of adult rats, suggesting that MCH may participate in stem cellrenewal and/or differentiation of early spermatocytes; Hervieu et al.,Biology of Reduction 54:1161-1172, (1996). MCH injected directly intothe medial preoptic area (MPOA) or ventromedial nucleus (VMN) stimulatedsexual activity in female rats; Gonzalez et al., Peptides 17:171-177,(1996). In ovariectomized rats primed with estradiol, MCH stimulatedluteinizing hormone (LH) release while anti-MCH antiserum inhibited LHrelease; Gonzalez et al., Neuroendocrinology 66:254-262, (1997). Thezona incerta, which contains a large population of MCH cell bodies, haspreviously been identified as a regulatory site for the pre-ovulatory LHsurge; MacKenzie et al., Neuroendocrinology 39:289-295, (1984). MCH hasbeen reported to influence release of pituitary hormones including ACTHand oxytocin. MCH analogues may also be useful in treating epilepsy. Inthe PTZ seizure model, injection of MCH prior to seizure inductionprevented seizure activity in both rats and guinea pigs, suggesting thatMCH-containing neurons may participate in the neural circuitryunderlying PTZ-induced seizure; Knigge and Wagner, Peptides18:1095-1097, (1997). MCH has also been observed to affect behavioralcorrelates of cognitive functions. MCH treatment hastened extinction ofthe passive avoidance response in rats; McBride et al., Peptides15:757-759, (1994); raising the possibility that MCH receptorantagonists may be beneficial for memory storage and/or retention. Apossible role for MCH in the modulation or perception of pain issupported by the dense innervation of the periaqueductal grey (PAG) byMCH-positive fibers. Finally, MCH may participate in the regulation offluid intake. ICV infusion of MCH in conscious sheep produced diuretic,natriuretic, and kaliuretic changes in response to increased plasmavolume; Parkes, J. Neuroendocrinol. 8:57-63, (1996). Together withanatomical data reporting the presence of MCH in fluid regulatory areasof the brain, the results indicate that MCH may be an important peptideinvolved in the central control of fluid homeostasis in mammals.

In a recent citation MCHR1 antagonists surprisingly demonstrated theiruse as an anti-depressants and/or anti-anxiety agents. MCHR1 antagonistshave been reported to show antidepressant and anxiolytic activities inrodent models, such as, social interaction, forced swimming test andultrasonic vocalization. Therefore, MCHR1 antagonists could be useful toindependently treat subjects with depression and/or anxiety. Also, MCHR1antagonists could be useful to treat subjects that suffer fromdepression and/or anxiety and obesity.

This invention provides a method of treating an abnormality in a subjectwherein the abnormality is alleviated by decreasing the activity of amammalian MCH1 receptor which comprises administering to the subject anamount of a compound which is a mammalian MCH1 receptor antagonisteffective to treat the abnormality. In separate embodiments, theabnormality is a regulation of a steroid or pituitary hormone disorder,an epinephrine release disorder, an anxiety disorder, gentagastrointestinal disorder, a cardiovascular disorder, an electrolytebalance disorder, hypertension, diabetes, a respiratory disorder,asthma, a reproductive function disorder, an immune disorder, anendocrine disorder, a musculoskeletal disorder, a neuroendocrinedisorder, a cognitive disorder, a memory disorder, a sensory modulationand transmission disorder, a motor coordination disorder, a sensoryintegration disorder, a motor integration disorder, a dopaminergicfunction disorder, a sensory transmission disorder, an olfactiondisorder, a sympathetic innervation disorder, an affective disorder, astress-related disorder, a fluid-balance disorder, a seizure disorder,pain, psychotic behavior, morphine tolerance, opiate addiction ormigraine.

Compositions of the invention may conveniently be administered in unitdosage form and may be prepared by any of the methods well known in thepharmaceutical art, for example, as described in Remington'sPharmaceutical Sciences (Mack Pub. Co., Easton, Pa., 1980).

The compounds of the invention can be employed as the sole active agentin a pharmaceutical or can be used in combination with other activeingredients which could facilitate the therapeutic effect of thecompound.

Compounds of the present invention or a solvate or physiologicallyfunctional derivative thereof can be used as active ingredients inpharmaceutical compositions, specifically as a MCH receptor antagonists.By the term “active ingredient” is defined in the context of a“pharmaceutical composition” and shall mean a component of apharmaceutical composition that provides the primary pharmaceuticalbenefit, as opposed to an “inactive ingredient” which would generally berecognized as providing no pharmaceutical benefit. The term“pharmaceutical composition” shall mean a composition comprising at oneactive ingredient and at least one ingredient that is not an activeingredient (for example and not limitation, a filler, dye, or amechanism for slow release), whereby the composition is amenable to usefor a specified, efficacious outcome in a mammal (for example, and notlimitation, a human).

Pharmaceutical compositions, including, but not limited to,pharmaceutical compositions, comprising at least one compound of thepresent invention and/or an acceptable salt or solvate thereof (e.g., apharmaceutically acceptable salt or solvate) as an active ingredientcombined with at least one carrier or excipient (e.g., pharmaceuticalcarrier or excipient) may be used in the treatment of clinicalconditions for which a MCH receptor antagonist is indicated. At leastone compound of the present invention may be combined with the carrierin either solid or liquid form in a unit dose formulation. Thepharmaceutical carrier must be compatible with the other ingredients inthe composition and must be tolerated by the individual recipient. Otherphysiologically active ingredients may be incorporated into thepharmaceutical composition of the invention if desired, and if suchingredients are compatible with the other ingredients in thecomposition. Formulations may be prepared by any suitable method,typically by uniformly mixing the active compound(s) with liquids orfinely divided solid carriers, or both, in the required proportions, andthen, if necessary, forming the resulting mixture into a desired shape.

Conventional excipients, such as binding agents, fillers, acceptablewetting agents, tabletting lubricants, and disintegrants may be used intablets and capsules for oral administration. Liquid preparations fororal administration may be in the form of solutions, emulsions, aqueousor oily suspensions, and syrups. Alternatively, the oral preparationsmay be in the form of dry powder that can be reconstituted with water oranother suitable liquid vehicle before use. Additional additives such assuspending or emulsifying agents, non-aqueous vehicles (including edibleoils), preservatives, and flavorings and colorants may be added to theliquid preparations. Parenteral dosage forms may be prepared bydissolving the compound of the invention in a suitable liquid vehicleand filter sterilizing the solution before filling and sealing anappropriate vial or ampoule. These are just a few examples of the manyappropriate methods well known in the art for preparing dosage forms.

It is noted that when the MCH receptor antagonists are utilized asactive ingredients in a pharmaceutical composition, these are notintended for use only in humans, but in other non-human mammals as well.Indeed, recent advances in the area of animal health-care mandate thatconsideration be given for the use of MCH receptor antagonists for thetreatment of obesity in domestic animals (e.g., cats and dogs), and MCHreceptor antagonists in other domestic animals where no disease ordisorder is evident (e.g., food-oriented animals such as cows, chickens,fish, etc.). Those of ordinary skill in the art are readily creditedwith understanding the utility of such compounds in such settings.

Pharmaceutically acceptable salts of the compounds of the invention canbe prepared by reacting the free acid or base forms of these compoundswith the appropriate base or acid in water, in an organic solvent, or ina mixture of the two; generally, nonaqueous media like ether, ethylacetate, ethanol, isopropanol, dioxane, or acetonitrile are preferred.For instance, when the compound (I) possesses an acidic functionalgroup, it can form an inorganic salt such as an alkali metal salt (e.g.,sodium salt, potassium salt, etc.), an alkaline earth metal salt (e.g.calcium salt, magnesium salt, barium salt, etc.), and an ammonium salt.When the compound (I) possesses a basic functional group, it can form aninorganic salt (e.g., hydrochloride, sulfate, phosphate, hydrobromate,etc.) or an organic salt (e.g., acetate, maleate, fumarate, succinate,methanesulfonate, p-toluenesulfonate, citrate, tartrate, etc.).

When a compound of the invention contains optical isomers,stereoisomers, regio isomers, rotational isomers, a single substance anda mixture of them are included as a compound of the invention. Forexample, when a chemical formula is represented as showing nostereochemical designation(s), such as Formula IX, then all possiblestereoisomer, optical isomers and mixtures thereof are considered withinthe scope of that formula. Accordingly, Formula XXII, specificallydesignates the cis relationship between the two amino groups on thecyclohexyl ring and therefore this formula is also fully embraced byFormula IX.

The novel substituted quinazolines of the present invention can bereadily prepared according to a variety of synthetic manipulations, allof which would be familiar to one skilled in the art. Preferred methodsfor the preparation of compounds of the present invention include, butare not limited to, those described in Scheme 1-31.

The common intermediate (E) of the novel substituted quinazolines can beprepared as shown in Scheme 1. Commercially available1H,3H-quinazoline-2,4-dione (A) is converted to 2,4-dihalo-quinazoline(B) by a halogenating agent with or without a base (wherein X is halogensuch as chloro, bromo, or iodo). The halogenating agent includesphosphorous oxychloride (POCl₃), phosphorous oxybromide (POBr₃), orphosphorus pentachloride (PCl₅). The base includes a tertiary amine(preferably N,N-diisopropylethylamine, etc.) or an aromatic amine(preferably N,N-dimethylaniline, etc.). Reaction temperature ranges fromabout 100° C. to 200° C., preferably about 140° C. to 180° C. Thehalogen of 4-position of 2,4-dihalo-quinazoline (B) is selectivelysubstituted by a primary or secondary amine (HNR_(2a)R_(2b), whereinR_(2a) and R_(2b) are as defined above) with or without a base in aninert solvent to provide the corresponding 4-substitued amino adduct(C). The base includes an alkali metal carbonate (preferably sodiumcarbonate or potassium carbonate, etc.), an alkali metal hydroxide(preferably sodium hydroxide, etc.), or a tertiary amine (preferablyN,N-diisopropylethylamine, triethylamine, or N-methylmorpholine, etc.).The inert solvent includes lower alkyl alcohol solvents (preferablymethanol, ethanol, 2-propanol, or butanol, etc.), ethereal solvents(preferably tetrahydrofuran or dioxane, etc.), or amide solvents(preferably N,N-dimethylformamide or 1-methyl-pyrrolidin-2-one, etc.).Reaction temperature ranges from about 0° C. to 200° C., preferablyabout 10° C. to 150° C.

In turn, this is substituted by the mono-protected diamine (R₄HN-A-NR₅P,wherein R₄HN-A-NR₅P is as defined below, R₄ and R₅ are as defined above,and P is a protective group) with or without a base in an inert solventto provide 2,4-disubstituted amino quinazoline (D). The base includes analkali metal carbonate (preferably sodium carbonate or potassiumcarbonate, etc.), an alkali metal hydroxide (preferably sodiumhydroxide, etc.), or a tertiary amine (preferablyN,N-diisopropylethylamine, triethylamine, or N-methylmorpholine, etc.).The inert solvent includes lower alkyl alcohol solvents (preferablymethanol, ethanol, 2-propanol, or butanol, etc.) or amide solvents(preferably N,N-dimethylformamide or 1-methyl-pyrrolidin-2-one, etc.).Reaction temperature ranges from about 50° C. to 200° C., preferablyabout 80° C. to 150° C. Also this reaction can be carried out undermicrowave conditions. Representative protecting groups suitable for awide variety of synthetic transformations are disclosed in Greene andWuts, Protective Groups in Organic Synthesis, second edition, John Wiley& Sons, New York, 1991, the disclosure of which is incorporated hereinby reference in its entirety. The deprotection of the protective groupleads to the common intermediate (E) of the novel substitutedquinazolines.

R₄HN-A-NR₅P is;

The conversion of the common intermediate (E) to the novel substitutedquinazolines (F-H) of the present invention is outlined in Scheme 2.

The amine (E) is reacted with a sulfonyl chloride (R₁SO₂Cl) and a basein an inert solvent to provide the novel sulfonamide (F) of the presentinvention. The base includes an alkali metal carbonate (preferablysodium carbonate or potassium carbonate, etc.), an alkali metalhydrogencarbonate (preferably sodium hydrogencarbonate or potassiumhydrogencarbonate, etc.), an alkali hydroxide (preferably sodiumhydroxide or potassium hydroxide, etc.), a tertiary amine (preferablyN,N-diisopropylethylamine, triethylamine, or N-methylmorpholine, etc.),or an aromatic amine (preferably pyridine or imidazole, etc.). The inertsolvent includes lower halocarbon solvents (preferably dichloromethane,dichloroethane, or chloroform, etc.), ethereal solvents (preferablytetrahydrofuran or dioxane), alcohol solvents (preferably 2-propanol,etc.), or aromatic solvents (preferably toluene or pyridine, etc.).Reaction temperature ranges from about −20° C. to 50° C., preferablyabout 0° C. to 40° C.

The amine (E) is reacted with a carboxylic acid (R₁CO₂H) and adehydrating condensing agent in an inert solvent with or without a baseto provide the novel amide (G) of the present invention. The dehydratingcondensing agent includes dicyclohexylcarbodiimide (DCC),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC.HCl),bromo-tris-pyrrolidino-phosnium hexafluorophosphate (PyBroP),O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (HATU), or1-cyclohexyl-3-methylpolystyrene-carbodiimide. The base includes atertiary amine (preferably N,N-diisopropylethylamine or triethylamine,etc.). The inert solvent includes lower halocarbon solvents (preferablydichloromethane, dichloroethane, or chloroform, etc.), ethereal solvents(preferably tetrahydrofuran or dioxane), nitrile solvents (preferablyacetonitrile, etc.), or amide solvents (preferablyN,N-dimethylformamide, etc.). In case of need, 1-hydroxybenzotriazole(HOBT), HOBT-6-carboxaamidomethyl polystyrene, or1-hydroxy-7-azabenzotriazole (HOAT) can be used as a reactant agent.Reaction temperature ranges from about −20° C. to 50° C., preferablyabout 0° C. to 40° C.

Alternatively, the novel amide (G) of the present invention can beobtained by amidation reaction using an acid chloride (R₁COCl) and abase in an inert solvent. The base includes an alkali metal carbonate(preferably sodium carbonate or potassium carbonate, etc.), an alkalimetal hydrogencarbonate (preferably sodium hydrogencarbonate orpotassium hydrogencarbonate, etc.), an alkali hydroxide (preferablysodium hydroxide or potassium hydroxide, etc.), a tertiary amine(preferably N,N-diisopropylethylamine, triethylamine, orN-methylmorpholine, etc.), or an aromatic amine (preferably pyridine,imidazole, poly-(4-vinylpyridine), etc.). The inert solvent includeslower halocarbon solvents (preferably dichloromethane, dichloroethane,or chloroform, etc.), ethereal solvents (preferably tetrahydrofuran ordioxane), amide solvents (preferably N,N-dimethylformamide, etc.), oraromatic solvents (preferably toluene or pyridine, etc.). Reactiontemperature ranges from about −20° C. to 50° C., preferably about 0° C.to 40° C.

The novel amide (G) of the present invention is reacted with a reducingagent in an inert solvent to provide the novel amine (H) of the presentinvention. The reducing agent includes alkali metal aluminum hydrides(preferably lithium aluminum hydride), alkali metal borohydrides(preferably lithium borohydride), alkali metal trialkoxyaluminumhydrides (preferably lithium tri-tert-butoxyaluminum hydride),dialkylaluminum hydrides (preferably di-isobutylaluminum hydride),borane, dialkylboranes (preferably di-isoamyl borane), alkali metaltrialkylboron hydrides (preferably lithium triethylboron hydride). Theinert solvent includes ethereal solvents (preferably tetrahydrofuran ordioxane) or aromatic solvents (preferably toluene, etc.). Reactiontemperature ranges from about −78° C. to 200° C., preferably about 50°C. to 120° C.

Alternatively, the novel amine (H) of the present invention can beobtained by reductive amination reaction using aldehyde (R₁CHO) and areducing agent in an inert solvent with or without an acid. The reducingagent includes sodium triacetoxyborohydride, sodium cyanoborohydride,sodium borohydride, or boran-pyridine complex, preferably sodiumtriacetoxyborohydride or sodium cyanoborohydride. The inert solventincludes lower alkyl alcohol solvents (preferably methanol or ethanol,etc.), lower halocarbon solvents (preferably dichloromethane,dichloroethane, or chloroform, etc.), ethereal solvents (preferablytetrahydrofuran or dioxane), or aromatic solvents (preferably toluene,etc.). The acid includes an inorganic acid (preferably hydrochloric acidor sulfuric acid) or an organic acid (preferably acetic acid). Reactiontemperature ranges from about −20° C. to 120° C., preferably about 0° C.to 100° C. Also this reaction can be carried out under microwaveconditions.

Compounds of Formula (I) can be prepared as shown in Scheme 3. The amineof commercially available trans-4-aminomethyl-cyclohexancarboxylic acidis protected as tert-butyl carbamate. The carboxylic acid is reduced tothe alcohol by sodium borohydride via the mixed acid anhydride.Tosylation of the alcohol with tosylchloride followed by azidation givethe adide, which is converted to the amine by lithium aluminum hydridereduction. The coupling of the amine with the quinazoline core (C),which is synthesized in Scheme 1, gives 2,4-disubstituted aminoquinazoline. The deprotection of Boc-group is achieved by an acid togive compounds of Formula (I).

Compounds of Formula (K) can be prepared as shown in Scheme 4. Knowncis-(4-aminomethyl-cyclohexylmethyl)-carbamic acid tert-butyl ester (J),synthesis of which is described in WO 01/2710, can be leaded tocompounds of Formula (K) according to the method of scheme 3.

Compounds of Formula (L) can be prepared as shown in Scheme 5. The amineof cis-[4-(2-amino-ethyl)-cyclohexyl]-carbamic acid tert-butyl ester isprotected as benzyl carbamate. The deprotection of Boc-group is achievedby an acid to give the amine. The coupling of the amine with quinazolinecore (C), which is synthesized as scheme 1, gives 2,4-disubstitutedamino quinazoline. The deprotection of Z-group is achieved by hydrogenreduction to give compounds of Formula (L).

Compounds of Formula (N) can be prepared as shown in Scheme 6. The amineof commercially available trans-4-aminomethyl-cyclohexanecarboxylic acidis protected as tert-butyl carbamate. The carboxylic acid is transformedto benzyl carbamate (M) by curtius rearrangement. The deprotection ofZ-group is achieved by hydrogen reduction to give the amine. The amineis converted to compounds of Formula (N) according to the method ofscheme 3.

Compounds of Formula (O) can be prepared from the compound of Formula(M), which is described in Scheme 6, as shown in Scheme 7. The compoundof Formula (M) can be leaded to compounds of Formula (O) according tothe method of scheme 5.

Compounds of Formula (Q) can be prepared as shown in Scheme 8.[4-(Benzyloxycarbonylamino-methyl)-cyclohexyl]-carbamic acid tert-butylester (P), synthesis of which is described in WO 01/72710, can be leadedto compounds of Formula (Q) according to the method of scheme 5.

Alternatively compounds of Formula (Q) can be prepared as shown inScheme 9. The amine of commercially availablecis-4-amino-cyclohexanecarboxylic acid is protected as tert-butylcarbamate. The carboxylic acid (R) is converted to the amide (S) byaqueous ammonia via the mixed acid anhydride. The deprotection ofBoc-group is achieved by an acid to give the amine. The coupling of theamine with quinazoline core (C), which is synthesized as scheme 1, gives2,4-disubstituted amino quinazoline. The amide is reduced to compoundsof Formula (Q).

Compounds of Formula (T) can be prepared from the compound of Formula(P), which is described in Scheme 8, as shown in Scheme 10. The compoundof Formula (P) can be leaded to compounds of Formula (T) according tothe method of scheme 6.

Alternatively compounds of Formula (T) can be prepared as shown inScheme 11. The amide (S), which is described in Scheme 9, is reduced tothe amine. The amine can be leaded to compounds of Formula (T) accordingto the method of scheme 3.

Compounds of Formula (V) can be prepared as shown in Scheme 12. Themono-protection of commercially available trans-cyclohexane-1,4-diaminecan be achieved by the method described in Synthetic communications, 20,2559-2564 (1990). The conversion to compounds of Formula (V) can beaccomplished according to the method of scheme 3.

Compounds of Formula (X) can be prepared as shown in Scheme 13. Thedicarboxylic acid of commercially availablecis-cyclohexane-1,4-dicarboxylic acid is transformed to dibenzylcarbamate by curtius rearrangement. The deprotection of Z-group isachieved by hydrogen reduction to give the diamine. The mono-protectionof the diamine can be achieved according to the method of scheme 12 togive the compound (W). The conversion to compounds of Formula (X) can beaccomplished according to the method of scheme 3.

Alternatively the compound of Formula (W) can be prepared as shown inScheme 14. The carboxylic acid (R), which is described in Scheme 9, istransformed to benzyl carbamate by curtius rearrangement. Thedeprotection of Z-group is achieved by hydrogen reduction to give thecompound of Formula (W).

Compounds of Formula (Y) can be prepared according to the methoddescribed in Scheme 12 by using commercially available4-aminomethyl-benzylamine as a starting material (Scheme 15).

Compounds of Formula (A′) can be prepared as shown in Scheme 16. Themono-protection of commercially available 4-aminomethyl-phenylamine canbe achieved by using an equimolecular amount of (Boc)₂O to givemono-tert-butyl carbamate (Z). The amine can be leaded to compounds ofFormula (A′) according to the method of scheme 3.

Compounds of Formula (B′) can be prepared from the compound of Formula(Z), which is described in Scheme 16, as shown in Scheme 17. Thecompound of Formula (Z) can be leaded to compounds of Formula (B′)according to the method of scheme 5.

Compounds of Formula (C′) can be prepared according to the methoddescribed in Scheme 3 by using commercially available(4-amino-phenyl)-carbamic acid tert-butyl ester as a starting material(Scheme 18).

Compounds of Formula (E′) can be prepared as shown in Scheme 19. Theselective protection of the secondary amine in the presence of theprimary amine of commercially available 4-(aminomethyl)piperidin isachieved by the method described in Synthetic communications, 22,2357-2360 (1992) to give the amine (D′). The amine is converted tocompounds of Formula (E′) according to the method of scheme 3.

Compounds of Formula (F′) can be prepared from the compound of Formula(D′), which is described in Scheme 19, as shown in Scheme 20. Thecompound of Formula (D′) can be leaded to compounds of Formula (F′)according to the method of Scheme 5.

Compounds of Formula (G′) can be prepared according to the methoddescribed in Scheme 5 by using commercially available1-benzyl-piperidin-4-ylamine as a starting material (Scheme 21).

Compounds of Formula (H′) can be prepared as shown in Scheme 22. Theamine of commercially available 1-benzyl-piperidin-4-ylamine isprotected as tert-butyl carbamate. The deprotection of benzyl group isachieved by hydrogen reduction to give the amine. The amine can beleaded to compounds of Formula (H′) according to the method of scheme 3.

Compounds of Formula (I′) can be prepared according to the methoddescribed in Scheme 3 by using commercially availablepyrrolidin-3-yl-carbamic acid tert-butyl ester as a starting material(Scheme 23).

Alternatively, the novel sulfonamide (F), the novel amide (G), and thenovel amine (H) of the present invention are directly synthesized fromthe quinazoline core (C), which is synthesized in Scheme 1, as shown inScheme 24. This coupling is performed with or without a base in an inertsolvent. The base includes an alkali metal carbonate (preferably sodiumcarbonate or potassium carbonate, etc.), an alkali metal hydroxide(preferably sodium hydroxide, etc.), or a tertiary amine (preferablyN,N-diisopropylethylamine, triethylamine, or N-methylmorpholine, etc.).The inert solvent includes lower alkyl alcohol solvents (preferablymethanol, ethanol, 2-propanol, or butanol, etc.) or amide solvents(preferably N,N-dimethylformamide or 1-methyl-pyrrolidin-2-one, etc.).Reaction temperature ranges from about 50° C. to 200° C., preferablyabout 80° C. to 180° C. Also this reaction can be carried out undermicrowave conditions.

Compounds of Formula (K′) can be prepared as shown in Scheme 25.Commercially available trans-4-aminomethyl-cyclohexanecarboxylic acid isreacted with sulfonyl chloride (R₁SO₂Cl) to give the sulfonamide. Thecarboxylic acid is converted to the amide via the mixed acid anhydride.The amide is reduced to the amine (J′) by borane reduction. The couplingof the amine with the quinazoline core (C), which is synthesized inScheme 1, gives the novel sulfonamide (K′) of the present invention.

Compounds of Formula (L′) can be prepared from the compound of Formula(U), which is described in Scheme 12, as shown in Scheme 26. The amine(U) is reacted with sulfonyl chloride (R₁SO₂Cl) to give the sulfonamide.The deprotection of Boc-group is achieved by an acid to give the amine.The coupling of the amine with quinazoline core (C), which issynthesized as scheme 1, gives the novel sulfonamide (L′) of the presentinvention.

Compounds of Formula (M′) can be prepared according to the methoddescribed in Scheme 26 by using the compound of Formula (D′), which isdescribed in Scheme 19, as a starting material (Scheme 27).

Compounds of Formula (N′) can be prepared according to the methoddescribed in Scheme 26 by using commercially availablepyrrolidin-3-yl-carbamic acid tert-butyl ester as a starting material(Scheme 28).

Compounds of Formula (O) can be prepared from the compound of Formula(Z), which is described in Scheme 16, as shown in Scheme 29. The aniline(Z) is reacted with carboxylic acid (R₁CO₂H) to give the amide. Thedeprotection of Boc-group is achieved by an acid to give the amine. Thecoupling of the amine with quinazoline core (C), which is synthesized asscheme 1, gives the novel sulfonamide (O′) of the present invention.

Compounds of Formula (P′) can be prepared as shown in Scheme 30. Theamine (W), which is synthesized in Scheme 13, is subjected to reductiveamination by aldehyde (R₁CHO). The deprotection of Boc-group is achievedby an acid to give the amine. The coupling of the amine with quinazolinecore (C), which is synthesized as scheme 1, gives the novel amine (P′)of the present invention.

Scheme 31 shows the preparation of compounds (Q′) of the invention whereQ of Formula I has Formula III. The compound (J′), which is synthesizedin Scheme 25, is reacted with (1-tert-butoxycarbonylamino-1trifluorometlanesulfonylimino-methyl)-carbamic acid tert-butyl ester.The deprotection of Boc-group is achieved by an acid to give the novelguanidine (Q′) of the present invention.

EXAMPLES

The compounds of the invention and their synthesis are furtherillustrated by the following examples. The following examples areprovided to further define the invention without, however, limiting theinvention to the particulas of these examples. “Ambient temperature” asreferred to in the following example is meant to indicate a temperaturefalling between 0° C. and 40° C.

Abbreviations used in the instant specification, particularly theSchemes and Examples, are as follows:

¹H NMR: proton nuclear magnetic resonance spectrum

AcOH: acetic acid

APCI: atmospheric pressure chemical ionization

(Boc)₂O: di-tertiary-butyl dicarbonate

BuLi: butyl lithium

BuOH: butanol

CaCl₂: calcium chloride

CDCl₃: deuterated chloroform

CF₃CO₂H: trifluoroacetic acid

CH₂Cl₂: dichloromethane

CHCl₃: chloroform

CI: chemical ionization

CuCl: copper (1) chloride

D₂O: deuterium oxide

DMAP: 4-dimethylaminopyridine

DMF: N,N-dimethylformamide

DMSO: dimethyl sulfoxide

EDC: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride

ESI: electrospray ionization

Et₂O: diethyl ether

EtOAc: acetic acid ethyl ester

EtOH: ethanol

FAB: fast atom bombardment

H₂SO₄: sulfuric acid

HATU:O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium-hexafluorophosphate

HCHO: formaldehyde

HCl: hydrogen chloride

HOAt: 1-hydroxy-7-azabenzotriazole

HOBt: 1-hydroxybenzotriazole

HPLC: high performance liquid chromatography

K₂CO₃: potassium carbonate

KHSO₄: potassium bisulfate

Me₂NH: dimethylamine

MeNH₂: methylamine

MeOH: methanol

MgSO₄: magnesium sulfate

Na₂CO₃: sodium carbonate

Na₂SO₄.10H₂O: sodium sulfate decahydrate

NaBH(OAc)₃: sodium triacetoxyborohydride

NaBH₃CN: sodium cyanoborohydride

NaBH₄: sodium borohydride

NaHCO₃: sodium hydrogencarbonate

NaN₃: sodium azide

NaNO₂: sodium nitrate

Pd(OH)₂: palladium hydroxide

Pd/C: palladium carbon

POCl₃: phosphoryl chloride

PVP: poly(4-vinylpyridine)

PyBroP: bromo-tris-pyrrolidino phosphonium hexafluoro phosphate

SOCl₂: thionyl chloride

t-BuOH: tertiary butanol

TFA: trifluoroacetic acid

THF: tetrahydrofuran

WSC: water solubule carbodiimide

ZCl: benzyloxycarbonyl chloride

s: singlet

d: doublet

t: triplet

q: qualtet

dd: doublet doublet

dt: doublet triplet

ddd: doublet doublet doublet

brs: broad singlet

m: multiplet

J: coupling constant

Hz: Hertz

The analytical condition of high performance liquid chromatography is asfollows:

-   -   -   Solvent A: 0.050% TFA in water        -   Solvent B: 0.035% TFA in acetonitrile        -   5-100% B over 5 min, flow rate 3.5 ml/min

Example 1

trans-4-Bromo-N-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-cyclohexylmethyl}-2-trifluoromethoxy-benzenesulfonamide

Step A: Synthesis of 2,4-dichloro-quinazoline.

To a suspension of 1H-quinazoline-2,4-dione (150 g, 925 mmol) in POCl₃(549 mL, 5.89 mol) was added dimethyl-phenyl-amine (123 mL, 962 mmol).The mixture was stirred at reflux for 7 hr and concentrated. Thesolution was poured into ice water, and the aqueous layer was extractedwith CHCl₃ (three times). The combined organic layer was dried overMgSO₄, filtered, concentrated, and purified by flash chromatography(silica gel, 50% CHCl₃ in hexane to 10% EtOAc in CHCl₃) to give2,4-dichloro-quinazoline (159 g, 86%) as a pale yellow solid.

CI MS m/e 199, M⁺; ¹H NMR (300 MHz, CDCl₃) δ 8.27 (dt, J=8.3, 1.1 Hz, 1H), 7.95-8.04 (m, 2 H), 7.71-7.81 (m, 1 H).

Step B: Synthesis of (2-chloro-quinazolin-4-yl)-dimethyl-amine.

A solution of 2,4-dichloro-quinazoline (102 g, 530 mmol) in THF (1.2 L)was cooled to 4° C. and 50% aqueous Me₂NH (139 mL, 1.33 mol) was added.The mixture was stirred at ambient temperature for 80 min. The solutionwas alkalized with saturated aqueous NaHCO₃ (pH=9), and the aqueouslayer was extracted with CHCl₃ (three times). The combined organic layerwas dried over MgSO₄, filtered, and concentrated. The residue wassuspended in 50% Et₂O in hexane (250 mL) and stirred at ambienttemperature for 30 min. The solid was collected by filtration, washedwith 50% Et₂O in hexane, and dried at 80° C. to give(2-chloro-quinazolin-4-yl)-dimethyl-amine (104 g, 94%) as a pale yellowsolid.

ESI MS m/e 207, M⁺; ¹H NMR (300 MHz, CDCl₃) δ 8.00 (d, J=8.4 Hz, 1 H),7.73-7.78 (m, 2 H), 7.68 (ddd, J=8.4, 6.9, 1.4 Hz, 1 H), 3.41 (s, 6 H).

Step C: Synthesis oftrans-4-(tert-butoxycarbonylamino-methyl)-cyclohexanecarboxylic acid.

To a solution of trans-4-aminomethyl-cyclohexanecarboxylic acid (150 g,954 mmol) in 1.32 M aqueous sodium hydroxide (750 mL) were added t-BuOH(1680 mL) and (Boc)₂O (215 g, 985 mmol). The reaction mixture wasstirred at ambient temperature for 18 hr. To the reaction mixture wasadded H₂O (2.8 L), and cooled at 5° C. The aqueous layer was acidifiedwith saturated aqueous KHSO₄ (pH=3), extracted with EtOAc (three times).The combined organic layer was washed with saturated aqueous NaRCO₃ andbrine, dried over MgSO₄, filtered, concentrated and dried under reducedpressure to givetrans-4-(tert-butoxycarbonylamino-methyl)-cyclohexanecarboxylic acid(165 g, 67%) as a white solid.

ESI MS m/e 280, M+Na⁺; ¹H NMR (300 MHz, CDCl₃) δ 4.60 (brs, 1 H), 2.98(t, J=6.3 Hz, 2 H), 2.19-2.33 (m, 1 H), 1.99-2.11 (m, 2 H), 1.77-1.90(m, 2 H), 1.44 (s, 9 H), 1.34-1.52 (m, 3 H), 0.86-1.05 (m, 2 H).

Step D: Synthesis of trans-(4-hydroxymethyl-cyclohexylmethyl)-carbamicacid tert-butyl ester.

A suspension oftrans-4-(tert-butoxycarbonylamino-methyl)-cyclohexane-carboxylic acid(155 g, 603 mmol) in CH₂Cl₂ (1.35 L) was cooled at −65° C. andtriethylamine (126 mL, 904 mmol) and a solution of ethyl chloroformate(58 mL, 751 mmol) in CH₂Cl₂ (200 mL) were added below −60° C. Thereaction mixture was stirred at 0° C. for 50 min. The mixture wasacidified with saturated aqueous KHSO₄ (pH=3), and the aqueous layer wasextracted with CHCl₃ (three times). The combined organic layer waswashed with saturated aqueous Na₂CO₃ and brine, dried over MgSO₄,filtered, and concentrated to give a colorless oil. A solution of theabove oil in THF (1.5 L) was cooled at −65° C. and NaBH₄ (26.6 g, 703mmol) and MeOH (45 mL) were added. The mixture was stirred at −40° C.for 25 min, and stirred at 4° C. for 3 hr. The mixture was acidifiedwith saturated aqueous KHSO₄ (pH=3), and the aqueous layer was extractedwith EtOAc (three times). The combined organic layer was washed withsaturated aqueous Na₂CO₃ and brine, dried over MgSO₄, filtered, andconcentrated, and purified by flash chromatography (silica gel, 17% MeOHin CHCl₃) to give trans-(4-hydroxymethyl-cyclohexylmethyl)-carbamic acidtert-butyl ester (123 g, 84%) as a white solid.

ESI MS m/e 266, M+Na⁺; ¹H NMR (300 MHz, CDCl₃) δ 4.59 (brs, 1 H), 3.46(d, J=6.4 Hz, 2 H), 2.98 (t, J=6.3 Hz, 2 H), 1.75-1.94 (m, 4 H), 1.45(s, 9 H), 1.24-1.70 (m, 3 H), 0.81-1.12 (m, 4 H).

Step E: Synthesis of trans-(4-azidomethyl-cyclohexylmethyl)-carbamicacid tert-butyl ester.

A solution of trans-(4-hydroxymethyl-cyclohexylmethyl)-carbamic acidtert-butyl ester (123 g, 505 mmol) in pyridine (1 L) was cooled at 4° C.and a solution of p-toluenesulfonyl chloride (125 g, 657 mmol) inpyridine (200 ml) was added below 10° C. The mixture was stirred atambient temperature for 15 hr and concentrated. After dissolution withEtOAc and H₂O, the organic layer was separated. The aqueous layer wasextracted with EtOAc (three times), the combined organic layer waswashed with H₂O, dried over MgSO₄, filtered, and concentrated to give apale yellow oil. To a solution of the above oil in DMF (1.6 L) was addedNaN₃ (98.8 g, 1.52 mol). The reaction mixture was stirred at ambienttemperature for 14 hr and concentrated. After dissolution with CHCl₃ andsaturated aqueous NaHCO₃, the organic layer was separated. The aqueouslayer was extracted with CHCl₃ (three times), the combined organic layerwas dried over MgSO₄, filtered, concentrated, and purified by flashchromatography (silica gel, 17% EtOAc in hexane) to givetrans-(4-azidomethyl-cyclohexylmethyl)-carbamic acid tert-butyl ester(124 g, 91%) as a colorless oil.

ESI MS m/e 291, M+Na⁺; ¹H NMR (300 MHz, CDCl₃) δ 4.59 (brs, 1 H), 3.13(d, J=6.5 Hz, 2 H), 2.98 (t, J=6.4 Hz, 2 H), 1.70-1.90 (m, 4 H), 1.44(s, 9 H), 1.25-1.65 (m, 2 H), 0.87-1.07 (m, 4 H).

Step F: Synthesis of trans-(4-aminomethyl-cyclohexylmethyl)-carbamicacid tert-butyl ester.

A suspension of lithium aluminum hydride (2.76 g, 72.6 mmol) in THF (225mL) was cooled at 0° C. and a solution oftrans-(4-azidomethyl-cyclohexylmethyl)-carbamic acid tert-butyl ester(15.0 g, 55.9 mmol) in THF (75 mL) was added over 1 hr. The reactionmixture was stirred at ambient temperature for 6 hr. The reaction wasquenched with Na₂SO₄.10H₂O, filtered through a pad of celite, andconcentrated. The residue was purified by flash chromatography (silicagel, 50% MeOH in CHCl₃) to givetrans-(4-aminomethyl-cyclohexylmethyl)-carbamic acid tert-butyl ester(12.3 g, 91%) as a pale yellow oil.

ESI MS m/e 243, M+H⁺; ¹H NMR (300 MHz, CDCl₃) δ 4.60 (brs, 1 H), 2.97(t, J=6.3 Hz, 2 H), 2.53 (d, J=6.4 Hz, 2 H), 1.70-1.92 (m, 4 H), 1.44(s, 9 H), 1.08-1.54 (m, 4 H), 0.81-1.02 (m, 4 H).

Step G: Synthesis oftrans-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-cyclohexylmethyl}-carbamicacid tert-butyl ester

A mixture of (2-chloro-quinazolin-4-yl)-dimethyl-amine (15.2 g, 73.3mmol) and trans-(4-aminomethyl-cyclohexylmethyl)-carbamic acidtert-butyl ester (14.8 g, 61.0 mmol) in 2-propanol (80 mL) was stirredat reflux for 4 days, poured into saturated aqueous NaHCO₃, and theaqueous layer was extracted with CHCl₃ (three times). The combinedorganic layer was dried over MgSO₄, filtered, concentrated, and purifiedby flash chromatography (NH-silica gel, 33% EtOAc in hexane) to givetrans-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-cyclohexylmethyl}-carbamicacid tert-butyl ester (20.4 g, 81%) as a pale yellow solid.

ESI MS m/e 414, M+H⁺; ¹H NMR (300 MHz, CDCl₃) δ7.81 (d, J=8.2 Hz, 1 H),7.40-7.52 (m, 2 H), 6.98-7.06 (m, 1 H), 4.93 (brs, 1 H), 4.59 (brs, 1H), 3.35 (t, J=6.2 Hz, 2 H), 3.26 (s, 6 H), 2.97 (t, J=6.2 Hz, 2 H),1.72-1.95 (m, 4 H), 1.44 (s, 9 H), 1.30-1.62 (m, 2 H), 0.84-1.12 (m, 4H).

Step H: Synthesis oftrans-4-bromo-N-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-cyclohexylmethyl}-2-trifluoromethoxy-benzenesulfonamidehydrochloride.

To a suspension oftrans-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]cyclohexylmethyl}-carbamicacid tert-butyl ester (3.84 g, 9.28 mmol) in EtOAc (50 mL) was added 4 Mhydrogen chloride in EtOAc (38 mL). The mixture was stirred at ambienttemperature for 40 min and concentrated to give a white solid. To asuspension of the solid in CH₂Cl₂ (50 mL) was addeddiisopropylethylamine (6.46 mL, 37.1 mmol). The mixture was cooled at 4°C. and a solution of 4-bromo-2-trifluoromethoxy-benzenesulfonyl chloride(3.31 g, 9.75 mmol) in CH₂Cl₂ (10 mL) was added below 5° C. The reactionmixture was stirred at 4° C. for 1.5 hr. The reaction was quenched withsaturated aqueous NaHCO₃ The aqueous layer was extracted with CHCl₃(three times). The combined organic layer was dried over MgSO₄,filtered, concentrated, and purified by flash chromatography (NH-silicagel, 20% EtOAc in hexane) to givetrans-4-bromo-N-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-cyclohexylmethyl}-2-trifluoromethoxy-benzenesulfonamide(3.45 g, 60%) as a pale yellow solid.

ESI MS m/e 616, M+H⁺; ¹H NMR (300 MHz, CDCl₃) δ 7.89 (d, J=8.9 Hz, 1 H),7.81 (d, J=7.6 Hz, 1 H), 7.35-7.61 (m, 4 H), 7.02 (t, J=6.8 Hz, 1 H),4.96 (brs, 1 H), 3.35 (t, J=6.1 Hz, 2 H), 3.26 (s, 6 H), 2.79 (d, J=6.7Hz, 2 H), 1.32-1.98 (m, 6 H), 0.72-1.12 (m, 4 H).

Example 2

trans-4-Bromo-N-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-cyclohexylmethyl}-2-trifluoromethoxy-benzenesulfonamidehydrochloride

Step A: Synthesis oftrans-4-bromo-N-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-cyclohexylmethyl}-2-trifluoromethoxy-benzenesulfonamidehydrochloride.

A solution oftrans-4-bromo-N-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-cyclohexylmethyl}-2-trifluoromethoxy-benzenesulfonamideobtained step H of example 1 (3.45 g, 5.61 mmol) in EtOAc (100 mL) wascooled on an ice-bath and 4 M hydrogen chloride in EtOAc (1.66 mL) wasadded. The mixture was stirred at ambient temperature for 1 hr andconcentrated to give a white solid. The solid was recrystallized from16% EtOH in Et₂O, and dried under reduced pressure to givetrans-4-bromo-N-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-cyclohexylmethyl}-2-trifluoromethoxy-benzenesulfonamidehydrochloride (2.76 g, 75%) as a white solid.

ESI MS m/e 616, M+H⁺; ¹H NMR (300 MHz, CDCl₃) δ 13.50 (brs, 1H), 8.42(t, J=6.0 Hz, 1 H), 7.86-7.94 (m, 2 H), 7.51-7.68 (m, 4H), 7.21-7.28 (m,1 H), 4.83 (d, J=6.4 Hz, 1 H), 3.51 (s, 6 H), 3.35 (t, J=6.0 Hz, 2H),2.78 (t, J=6.4 Hz, 2H), 1.73-1.95 (m, 4H), 1.35-1.65 (m, 2H), 0.81-1.12(m, 4H).

Example 3

trans-4-Bromo-N-9-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-cyclohexyl}-2-trifluoromethoxy-benzenesulfonamide

Step A: Synthesis oftrans-[4-(tert-butoxycarbonylamino-methyl)-cyclohexyl]-carbamic acidbenzyl ester.

To a suspension of trans-4-aminomethyl-cyclohexanecarboxylic acid (15.0g, 95.4 mmol) in CHCl₃ (150 mL) were added 1 M aqueous sodium hydroxide(150 mL) and (Boc)₂O (21.9 g, 100 mmol) successively. The reactionmixture was stirred at ambient temperature for 15 hr, and partitionedbetween CHCl₃ and water. The aqueous layer was acidified with saturatedaqueous KHSO₄ (pH=3), extracted with CHCl₃ (three times). The combinedorganic layer was washed with brine, dried over MgSO₄, filtered, andconcentrated to give a white solid. To a suspension of the above solidin benzene (75 mL) were added phosphorazidic acid diphenyl ester (16.2g, 58.9 mmol) and triethylamine (5.94 g, 58.7 mmol). The reactionmixture was stirred at reflux for 3 hr (Caution! Vigorous exothermicreaction). Benzyl alcohol (6.65 g, 61.5 mmol) was added, the reactionmixture was stirred at reflux for 24 hr, concentrated. After dissolutionwith EtOAc and H₂O, the organic layer was separated. The aqueous layerwas extracted with EtOAc (twice), the combined organic layer was washedwith 1 M aqueous KHSO₄, saturated aqueous NaHCO₃ and brine, dried overMgSO₄, filtered, concentrated, and purified by flash chromatography(silica gel, 33% EtOAc in hexane) to give a white solid. A suspension ofthe above solid in Et₂O was stirred at ambient temperature for 30 minand filtered. The filtrate was washed with Et₂O and dried under reducedpressure to givetrans-[4-(tert-butoxycarbonylamino-methyl)-cyclohexyl]-carbamic acidbenzyl ester (17.4 g, 50%) as a white solid.

ESI MS m/e 385, M+Na⁺; ¹H NMR (300 MHz, CDCl₃) δ 7.22-7.41 (m, 5 H),5.09 (s, 2 H), 4.20-4.68 (m, 2 H), 3.23-3.60 (m, 1 H), 2.96 (t, 2H,J=6.4 Hz), 1.62-2.18 (m, 4 H), 1.44 (s, 9 H), 1.30-1.60 (m, 1 H),0.90-1.23 (m, 4 H).

Step B: Synthesis of trans-(4-aminomethyl-cyclohexyl)-carbamic acidbenzyl ester hydrochloride.

To a suspension oftrans-[4-(tert-butoxycarbonylamino-methyl)-cyclohexyl]-carbamic acidbenzyl ester (4.00 g, 11.0 mmol) in EtOAc (40 mL) was added 4 M hydrogenchloride in EtOAc (10 mL). To the reaction mixture was added CHCl₃ (10mL) and the mixture was stirred at ambient temperature for 3 hr. To thereaction mixture was 4 M hydrogen chloride in EtOAc (20 mL) and themixture was stirred at ambient temperature for 1.5 hr, filtered, washedwith EtOAc, and dried under reduced pressure to givetrans-(4-aminomethyl-cyclohexyl)-carbamic acid benzyl esterhydrochloride (2.96 g, 90%) as a white solid.

ESI MS m/e 263, M (free)+H⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 8.12 (brs, 3H), 7.25-7.40 (m, 5 H), 7.21 (d, 1 H, J=7.8 Hz), 5.00 (s, 2 H),3.17-3.30 (m, 1 H), 2.62 (d, 2 H, J=7.0 Hz), 1.64-1.88 (m, 4 H),1.42-1.60 (m, 1 H), 0.90-1.21 (m, 4 H).

Step C: Synthesis oftrans-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-cyclohexyl}-carbamicacid benzyl ester.

A mixture of (2-chloro-quinazolin-4-yl)-dimethyl-amine (1.50 g, 7.22mmol) and trans-(4-aminomethyl-cyclohexyl)-carbamic acid benzyl esterhydrochloride (2.59 g, 8.67 mmol) in 2-propanol (15 mL) was stirred atreflux for 8 days and dissolved in CHCl₃ and MeOH. The mixture waspoured into saturated aqueous NaHCO₃, and the aqueous layer wasextracted with CHCl₃ (three times). The combined organic layer was driedover MgSO₄, filtered, concentrated, and purified by flash chromatography(H-silica gel, 33% EtOAc in hexane) to givetrans-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-cyclohexyl}-carbamicacid benzyl ester (1.20 g, 38%) as a pale yellow solid.

ESI MS m/e 434, M+H⁺; ¹H NMR (300 MHz, CDCl₃) δ 7.76-7.82 (m, 1 H),7.40-7.50 (m, 2 H), 7.25-7.40 (m, 5 H), 6.95-7.04 (m, 1 H), 5.08 (s, 2H), 4.82-5.05 (m, 1 H), 4.40-4.70 (m, 1 H), 3.40-3.60 (m, 1 H), 3.35 (t,2H, J=6.3 Hz), 3.26 (s, 6 H), 1.96-2.18 (m, 2 H), 1.80-1.96 (m, 2 H),1.45-1.61 (m, 1 H), 1.00-1.20 (m, 4 H).

Step D: Synthesis oftrans-4-bromo-N-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-cyclohexyl}-2-trifluoromethoxy-benzenesulfonamide.

To a suspension oftrans-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-cyclohexyl}-carbamicacid benzyl ester (500 mg, 1.15 mmol) in MeOH (5 mL) was added 5% Pd/C(50 mg). The mixture was stirred at ambient temperature under hydrogenatmosphere for 2 hr, at 50° C. for 8 hr, and at ambient temperature for10.5 hr, filtered, and concentrated to give a colorless oil. To asolution of the above oil in CH₂Cl₂ (5 mL) was addeddiisopropylethylamine (420 μL, 2.41 mmol). The mixture was cooled to 4°C. and a solution of 4-bromo-2-trifluoromethoxy-benzenesulfonyl chloride(431 mg, 1.27 mmol) in CH₂Cl₂ (2 mL) was added below 5° C. The reactionmixture was stirred at 4° C. for 1.5 hr. The reaction was quenched withsaturated aqueous NaHCO₃ The aqueous layer was extracted with CHCl₃(three times). The combined organic layer was dried over MgSO₄,filtered, concentrated, and purified by flash chromatography (NH-silicagel, 33% to 50% EtOAc in hexane) to givetrans-4-bromo-N-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-cyclohexyl}-2-trifluoromethoxy-benzenesulfonamide(560 mg, 81%) as a pale yellow solid.

ESI MS m/e 602, M+H⁺; ¹H NMR (300 MHz, CDCl₃) δ 7.90 (d, 1 H, J=8.9 Hz),7.80 (dd, 1 H, J=8.4, 0.9 Hz), 7.38-7.58 (m, 4 H), 7.01 (ddd, 1 H,J=8.4, 6.7, 1.6 Hz), 4.85-5.04 (m, 1 H), 3.31 (t, 2 H, J=6.3 Hz), 3.24(s, 6 H), 3.07-3.20 (m, 1 H), 1.70-1.90 (m, 4 H), 1.42-1.58 (m, 1 H),0.90-1.28 (m, 4 H).

Example 4

N²-[1-(4-Bromo-2-trifluoromethoxy-benzenesulfonyl)-piperidin-4-yl]-N⁴,N⁴-dimethyl-quinazoline-2,4-diamine

Step A: Synthesis ofIV-(1-benzyl-piperidin-4-yl)-N⁴,N⁴-dimethyl-quinazoline-2,4-diamine.

Using the procedure for the step G of example 1, the title compound wasobtained.

ESI MS m/e 362, M+H⁺; ¹H NMR (300 MHz, CDCl₃) δ 7.80 (d, J=7.6 Hz, 1 H),7.20-7.52 (m, 7 H), 6.97-7.05 (m, 1 H), 4.74-4.90 (m, 1 H), 3.90-4.05(m, 1 H), 3.53 (s, 2 H), 3.26 (s, 6 H), 2.78-2.90 (m, 2 H), 2.02-2.24(m, 4 H), 1.48-1.62 (m, 2 H).

Step B: Synthesis ofIV-[1-(4-bromo-2-trifluoromethoxy-benzenesulfonyl)-piperidin-4-yl]-N⁴,N⁴-dimethyl-quinazoline-2,4-diamine.

To a solution ofN²-(1-benzyl-piperidin-4-yl)-N⁴,N⁴-dimethyl-quinazoline-2,4-diamine (500mg, 1.38 mmol) in MeOH (5 mL) was added 20% Pd(OH)₂ (100 mg). Themixture was stirred at ambient temperature under hydrogen atmosphere for1.5 hr, at 50° C. for 8 hr, at ambient temperature for 16.5 hr, filteredthrough a pad of celite, and concentrated. To a solution of the residuein CH₂Cl₂ (5 mL) was added diisopropylethylamine (510 μL, 2.93 mmol).The mixture was cooled to 4° C. and a solution of4-bromo-2-trifluoromethoxy-benzenesulfonyl chloride (493 mg, 1.45 mmol)in CH₂Cl₂ (2 mL) was added below 5° C. The reaction mixture was stirredat 4° C. for 2 hr. The reaction was quenched with saturated aqueousNaHCO₃ The aqueous layer was extracted with CHCl₃ (three times). Thecombined organic layer was dried over MgSO₄, filtered, concentrated, andpurified by flash chromatography (NH-silica gel, 33% EtOAc in hexane) togiveN²-[1-(4-bromo-2-trifluoromethoxy-benzenesulfonyl)-piperidin-4-yl]-N⁴,N⁴-dimethyl-quinazoline-2,4-diamine(339 mg, 43%) as a pale yellow solid.

ESI MS m/e 596, M+Na⁺; ¹H NMR (300 MHz, CDCl₃) δ 7.87 (d, J=8.2 Hz, 1H), 7.81 (dd, J=8.3, 1.0 Hz, 1 H), 7.36-7.61 (m, 4 H), 7.04 (ddd, J=8.3,6.8, 1.4 Hz, 1 H), 4.77 (d, J=7.8 Hz, 1 H), 3.97-4.14 (m, 1 H),3.68-3.86 (m, 2 H), 3.25 (s, 6 H), 2.87-3.01 (m, 2 H), 2.10-2.23 (m, 2H), 1.51-1.70 (m, 2 H).

Example 5

trans-4-Bromo-N-[4-(4-dimethylamino-quinazolin-2-ylamino)-cyclohexyl]-2-trifluoromethoxy-benzenesulfonamide

Step A: Synthesis of trans-(4-amino-cyclohexyl)-carbamic acid tert-butylester.

To a solution of trans-cyclohexane-1,4-diamine (15.0 g, 131 mmol) in1,4-dioxane (85 mL) was added (Doc)₂O (3.61 g, 16.5 mmol) dropwise over4 hr. The mixture was stirred at ambient temperature for 19 hr andconcentrated. To the residue was added H₂O and the insoluble materialwas removed by filtration. The filtrate was extracted with CHCl₃ (threetimes). The combined organic layer was dried over MgSO₄, filtered,concentrated to give trans-(4-amino-cyclohexyl)-carbamic acid tert-butylester (3.15 g, 11% based on diamine, 89% based on (Boc)₂O) as a whitesolid.

ESI MS m/e 215, M+H⁺; ¹H NMR (300 MHz, CDCl₃) δ 4.43 (brs, 1 H), 3.36(brs, 1 H), 2.57-2.70 (m, 1 H), 1.78-2.04 (m, 4 H), 1.44 (s, 9 H),1.05-1.38 (m, 4 H).

Step B: Synthesis oftrans-[4-(4-dimethylamino-quinazolin-2-ylamino)-cyclohexyl]-carbamicacid tert-butyl ester.

Using the procedure for the step G of example 1, the title compound wasobtained

ESI MS m/e 408, M+Na⁺; ¹H NMR (300 MHz, CDCl₃) δ 7.80 (d, J=8.2 Hz, 1H), 7.39-7.52 (m, 2 H), 7.02 (ddd, 1H, J=8.3, 6.3, 1.9 Hz, 1 H),4.68-4.78 (m, 1 H), 4.43 (brs, 1 H), 3.89 (brs, 1 H), 3.46 (brs, 1 H),3.25 (s, 6 H), 2.15-2.24 (m, 2 H), 1.97-2.10 (m, 2 H), 1.45 (s, 9 H),1.21-1.35 (m, 4 H).

Step C: Synthesis oftrans-4-bromo-N-[4-(4-dimethylamino-quinazolin-2-ylamino)-cyclohexyl]-2-trifluoromethoxy-benzenesulfonamide.

To a solution oftrans-[4-(4-dimethylamino-quinazolin-2-ylamino)-cyclohexyl]-carbamicacid tert-butyl ester (500 mg, 1.30 mmol) in EtOAc (5 mL) was added 4 Mhydrogen chloride in EtOAc (5 mL). The mixture was stirred at ambienttemperature for 1 hr and concentrated to give a white solid. To asuspension of the above solid in CH₂Cl₂ (7 mL) was addeddiisopropylethylamine (905 μL, 5.20 mmol). The mixture was cooled to 4°C. and a solution of 4-bromo-2-trifluoromethoxy-benzenesulfonyl chloride(462 mg, 1.36 mmol) in CH₂Cl₂ (2 mL) was added below 5° C. The reactionmixture was stirred at 4° C. for 1.5 hr. To the reaction mixture wasadded a solution of 4-bromo-2-trifluoromethoxy-benzenesulfonyl chloride(88 mg, 0.26 mmol) in CH₂Cl₂ (0.5 mL) and the mixture was stirred at 4°C. for 1 hr. To the reaction mixture was added diisopropylethylamine(230 μL, 1.32 mmol) and the mixture was stirred at 4° C. for 1.5 hr. Thereaction was quenched with saturated aqueous NaHCO₃ The aqueous layerwas extracted with CHCl₃ (three times). The combined organic layer wasdried over MgSO₄, filtered, concentrated, and purified by flashchromatography (NH-silica gel, 50% EtOAc in hexane) to givetrans-4-bromo-N-[4-(4-dimethylamino-quinazolin-2-ylamino)-cyclohexyl]-2-trifluoromethoxy-benzenesulfonamid(339 mg, 44%) as a white solid.

ESI MS m/e 588, M+H⁺; ¹H NMR (300 MHz, CDCl₃) δ 7.92 (d, J=8.9 Hz, 1 H),7.80 (dd, J=8.3, 0.7 Hz, 1 H), 7.37-7.59 (m, 4 H), 6.99-7.06 (m, 1 H),4.64-4.75 (m, 1 H), 3.78-3.94 (m, 1 H), 3.17-3.30 (m, 7 H), 2.09-2.20(m, 2 H), 1.85-1.97 (m, 2 H), 1.12-1.47 (m, 4 H).

Example 6

trans-4-Bromo-N-[4-(4-dimethylamino-quinazolin-2-ylamino)-cyclohexylmethyl]-2-trifluoromethoxy-benzenesulfonamide

Step A: Synthesis of trans-(4-amino-cyclohexylmethyl)-carbamic acidtert-butyl ester.

To a suspension oftrans-[4-(tert-butoxycarbonylamino-methyl)-cyclohexyl]-carbamic acidbenzyl ester (4.00 g, 11.0 mmol) in MeOH (40 mL) was added 5% Pd/C (400mg). The mixture was stirred at ambient temperature under hydrogenatmosphere for 1 hr, filtered through a pad of celite, and concentratedto give a white solid. A suspension of the above solid in hexane (15 mL)was stirred at ambient temperature for 30 min. The solid was collectedby filtration, washed with hexane, dried under reduced pressure to givetrans-(4-amino-cyclohexylmethyl)-carbamic acid tert-butyl ester (2.52 g,100%) as a white solid.

ESI MS m/e 229, M+H⁺; ¹H NMR (300 MHz, CDCl₃) δ 4.56-4.88 (m, 1 H), 3.00(t, J=6.5 Hz, 2 H), 2.54-2.65 (m, 1 H), 1.70-1.94 (m, 4 H), 1.44 (s, 9H), 1.18-1.50 (m, 1 H), 0.92-1.15 (m, 4 H).

Step B: Synthesis oftrans-[4-(4-dimethylamino-quinazolin-2-ylamino)-cyclohexylmethyl]-carbamicacid tert-butyl ester.

Using the procedure for the step G of example 1, the title compound wasobtained

ESI MS m/e 422, M+Na⁺; ¹H NMR (300 MHz, CDCl₃) 7.81 (d, J=7.9 Hz, 1 H),7.38-7.52 (m, 2 H), 6.96-7.07 (m, 1 H), 4.55-4.84 (m, 2 H), 3.75-3.97(m, 1 H), 3.26 (s, 6 H), 3.01 (t, J=6.4 Hz, 2 H), 2.15-2.30 (m, 2 H),1.75-1.88 (m, 2 H), 1.45 (s, 9 H), 1.35-1.54 (m, 1 H), 1.00-1.30 (m, 4H).

Step C: Synthesis oftrans-4-bromo-N-[4-(4-dimethylamino-quinazolin-2-ylamino)-cyclohexylmethyl]-2-trifluoromethoxy-benzenesulfonamide.

To a suspension oftrans-[4-(4-dimethylamino-quinazolin-2-ylamino)-cyclohexylmethyl]-carbamicacid tert-butyl ester (500 mg, 1.25 mmol) in EtOAc (5 mL) was added 4 Mhydrogen chloride in EtOAc (5 mL). The mixture was stirred at ambienttemperature for 1 hr and concentrated to give a white solid. To asuspension of the above solid in CH₂Cl₂ (7 mL) was addeddiisopropylethylamine (905 μL, 5.20 mmol). The mixture was cooled to 4°C. and a solution of 4-bromo-2-trifluoromethoxy-benzenesulfonyl chloride(446 mg, 1.31 mmol) in CH₂Cl₂ (2 mL) was added below 5° C. The reactionmixture was stirred at 4° C. for 1.5 hr. To the reaction mixture wasadded a solution of 4-bromo-2-trifluoromethoxy-benzenesulfonyl chloride(85 mg, 0.25 mmol) in CH₂Cl₂ (0.5 mL) and the mixture was stirred at 4°C. for 1 hr. To the reaction mixture was added diisopropylethylamine(220 μL, 1.26 mmol) and the mixture was stirred at 4° C. for 1 hr. Thereaction was quenched with saturated aqueous NaHCO₃. The aqueous layerwas extracted with CHCl₃ (three times). The combined organic layer wasdried over MgSO₄, filtered, concentrated, and purified by flashchromatography (NH-silica gel, 50% EtOAc in hexane) to givetrans-4-bromo-N-[4-(4-dimethylamino-quinazolin-2-ylamino)-cyclohexylmethyl]-2-trifluoromethoxy-benzenesulfonamide(624 mg, 83%) as a pale yellow solid.

ESI MS m/e 602, M+H⁺; ¹H NMR (300 MHz, CDCl₃) δ 7.89 (d, J=8.9 Hz, 1 H),7.80 (d, J=8.5 Hz, 1 H), 7.39-7.60 (m, 4 H), 7.04 (ddd, J=8.2, 6.8, 1.6Hz, 1 H), 3.71-3.92 (m, 1 H), 3.30 (s, 6 H), 2.85 (d, J=6.5 Hz, 2 H),2.10-2.22 (m, 2 H), 1.70-1.86 (m, 2 H), 1.37-1.53 (m, 1 H), 0.98-1.32(m, 4 H).

Example 7

N²-[1-(4-Bromo-2-trifluoromethoxybenzenesulfonyl)-piperidin-4-ylmethyl]-N⁴,N⁴-dimethyl-quinazoline-2,4-diamine

Step A: Synthesis of 4-aminomethyl-piperidine-1-carboxylic acidtert-butyl ester.

To a solution of C-piperidin-4-yl-methylamine (15.0 g, 131 mmol) intoluene (165 mL) was added benzaldehyde (13.9 g, 131 mmol) and themixture was stirred at reflux with a Dean-Stark trap under N₂ atmospherefor 3 hr, and cooled on an ice-bath. To the reaction mixture was added(Boc)₂O (31.5 g, 144 mmol) dropwise over 15 min. The mixture was stirredat ambient temperature for 2.5 days, and concentrated. To the residuewas added 1 M aqueous KHSO₄ and the mixture was stirred at ambienttemperature for 7 hr, the aqueous layer was washed with EtO (twice),alkalized with sodium hydroxide, and extracted with CHCl₃ (five times).The combined organic layer was dried over MgSO₄, filtered, concentrated.The precipitate was suspended in hexane (10 mL) and the suspension wasstirred at ambient temperature for 10 min. The solid was collected byfiltration and dried under reduced pressure to give4-aminomethyl-piperidine-1-carboxylic acid tert-butyl ester (25.8 g,92%) as a white solid.

ESI MS m/e 215, M+H⁺; ¹H NMR (300 MHz, CDCl₃) δ 3.85-4.22 (m, 2 H), 2.90(d, J=6.8 Hz, 2 H), 2.50-2.80 (m, 2 H), 1.70-2.02 (m, 3 H), 1.45 (s, 9H), 1.10-1.28 (m, 2 H).

Step B: Synthesis of4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-piperidine-1-carboxylicacid tert-butyl ester.

Using the procedure for the step G of example 1, the title compound wasobtained

ESI MS m/e 386, M+H⁺; ¹H NMR (300 MHz, CDCl₃) δ 7.81 (d, J=8.4 Hz, 1 H),7.41-7.53 (m, 2 H), 6.99-7.06 (m, 1 H), 5.16 (brs, 1 H), 4.00-4.20 (m, 2H), 3.41 (t, J=6.1 Hz, 2 H), 3.26 (s, 6 H), 2.60-2.77 (m, 2 H),1.67-1.84 (m, 3 H), 1.45 (s, 9 H), 1.11-1.28 (m, 2 H).

Step C: Synthesis ofN²-[1-(4-bromo-2-trifluoromethoxy-benzenesulfonyl)-piperidin-4-ylmethyl]-N⁴,N⁴-dimethyl-quinazoline-2,4-diamine.

To a suspension of4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-piperidine-1-carboxylicacid tert-butyl ester (500 mg, 1.30 mmol) in EtOAc (5 mL) was added 4 Mhydrogen chloride in EtOAc (5 mL). The mixture was stirred at ambienttemperature for 1 hr and concentrated to give a white solid. To asuspension of the above solid in CH₂Cl₂ (5 mL) was addeddiisopropylethylamine (480 μL, 2.76 mmol). The mixture was cooled to 4°C. and a solution of 4-bromo-2-trifluoromethoxy-benzenesulfonyl chloride(462 mg, 1.36 mmol) in CH₂Cl₂ (2 mL) was added below 5° C. The reactionmixture was stirred at 4° C. for 3 hr. The reaction was quenched withsaturated aqueous NaHCO₃ The aqueous layer was extracted with CHCl₃(three times). The combined organic layer was dried over MgSO₄,filtered, concentrated, and purified by flash chromatography (NH-silicagel, 14% to 20% EtOAc in hexane) to giveN²-[1-(4-bromo-2-trifluoromethoxy-benzenesulfonyl)-piperidin-4-ylmethyl]-N⁴,N⁴-dimethyl-quinazoline-2,4-diamine(420 mg, 55%) as a yellow solid.

ESI MS m/e 588, M+H⁺, ¹H NMR (300 MHz, CDCl₃) δ 7.85 (d, J=8.9 Hz, 1 H),7.81 (dd, J=8.7, 0.9 Hz, 1 H), 7.40-7.56 (m, 4 H), 7.04 (ddd, J=8.2,6.7, 1.6 Hz, 1 H), 5.10-5.46 (brs, 1 H), 3.85 (d, J=12.4 Hz, 2 H), 3.40(t, J=6.4 Hz, 2 H), 3.27 (s, 6 H), 2.56-2.67 (m, 2 H), 1.64-1.91 (m, 3H), 1.23-1.43 (m, 2 H).

Example 8

4-Bromo-N-[1-(4-dimethylamino-quinazolin-2-yl)-piperidin-4-ylmethyl]-2-trifluoromethoxy-benzenesulfonamide

Step A: Synthesis of4-(benzyloxycarbonylamino-methyl)-piperidine-1-carboxylic acidtert-butyl ester.

To a solution of 4-aminomethyl-piperidine-1-carboxylic acid tert-butylester (7.00 g, 32.7 mmol) in CHCl₃ (70 mL) was added triethylamine (3.64g, 36.0 mmol). The resulting solution was cooled to 4° C. and ZCl (6.13g, 35.9 mmol) was added below 8° C. over 15 min. The reaction mixturewas stirred at ambient temperature for 18 hr, and poured into saturatedaqueous NaHCO₃. The aqueous layer was extracted with CHCl₃ (threetimes), dried over MgSO₄, filtered, concentrated, and purified by flashchromatography (silica gel, 33% to 50% EtOAc in hexane) to give4-(benzyloxycarbonylamino-methyl)-piperidine-1-carboxylic acidtert-butyl ester (10.7 g, 94%) as a colorless oil.

ESI MS m/e 371, M+Na⁺; ¹H NMR (300 MHz, CDCl₃) δ 7.26-7.37 (m, 5 H),5.09 (s, 2 H), 4.84-5.01 (m, 1 H), 3.95-4.22 (m, 2 H), 2.98-3.16 (m, 2H), 2.66 (t, J=12.4 Hz, 2 H), 1.58-1.72 (m, 3 H), 1.45 (s, 9 H),0.98-1.18 (m, 2 H).

Step B: Synthesis of piperidin-4-ylmethyl-carbamic acid benzyl esterhydrochloride.

A solution of 4-(benzyloxycarbonylamino-methyl)-piperidine-1-carboxylicacid tert-butyl ester (10.2 g, 29.3 mmol) in EtOAc (100 mL) was cooledon an ice-bath and 4 M hydrogen chloride in EtOAc (100 mL) was added.The mixture was stirred at ambient temperature for 1 hr andconcentrated. The residue was suspended in hexane (30 mL) and themixture was stirred at ambient temperature for 30 min. The solid wascollected by filtration, washed with hexane, and dried under reducedpressure to give piperidin-4-ylmethyl-carbamic acid benzyl esterhydrochloride (7.24 g, 87%) as a white solid.

ESI MS m/e 271, M (free)+Na⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 9.10 (brs, 2H), 7.20-7.50 (m, 6 H), 5.02 (s, 2 H), 3.15-3.28 (m, 2 H), 2.68-3.02 (m,4 H), 1.56-1.82 (m, 3 H), 1.20-1.52 (m, 2 H).

Step C: Synthesis of[1-(4-dimethylamino-quinazolin-2-yl)-piperidin-4-ylmethyl]-carbamic acidbenzyl ester.

Using the procedure for the step C of example 3, the title compound wasobtained

ESI MS m/e 420, M+H⁺; ¹H NMR (300 MHz, CDCl₃) δ 7.78 (d, J=8.2 Hz, 1 H),7.21-7.49 (m, 7 H), 6.95-7.04 (m, 1 H), 5.06-5.17 (m, 2 H), 4.83-4.98(m, 3 H), 3.24 (s, 6 H), 3.00-3.16 (m, 2 H), 2.77-2.91 (m, 2 H),1.58-1.97 (m, 3 H), 1.12-1.33 (m, 2 H).

Step D: Synthesis of4-bromo-N-[1-(4-dimethylamino-quinazolin-2-yl)-piperidin-4-ylmethyl]-2-trifluoromethoxy-benzenesulfonamide.

Using the procedure for the step D of example 3, the title compound wasobtained

ESI MS m/e 588, M+H⁺; ¹H NMR (300 MHz, CDCl₃) δ 7.87 (d, J=8.7 Hz, 1 H),7.78 (d, J=8.2 Hz, 1 H), 7.44-7.59 (m, 4 H), 6.97-7.06 (m, 1 H),4.94-5.04 (m, 1 H), 4.89 (d, J=13.2 Hz, 2 H), 3.25 (s, 6 H), 2.75-2.88(m, 4 H), 1.64-1.82 (m, 3 H), 1.05-1.28 (m, 2 H).

Example 9

cis-4-Bromo-N-[4-(4-dimethylamino-quinazolin-2-ylamino)-cyclohexyl]-2-trifluoromethoxy-benzenesulfonamide

Step A: Synthesis of cis-(4-benzyloxycarbonylamino-cyclohexyl)-carbamicacid benzyl ester.

To a suspension of cis-cyclohexane-1,4-dicarboxylic acid (25.0 g, 145mmol) in benzene (125 mL) were added phosphorazidic acid diphenyl ester(81.9 g, 298 mmol) and triethylamine (30.1 g, 297 mmol). The reactionmixture was stirred at reflux for 2.5 hr (Caution! Vigorous exothermicreaction). Benzyl alcohol (32.2 g, 298 mmol) was added and the mixturewas stirred at reflux for 24 hr. The reaction mixture was concentratedand the residue was dissolved in EtOAc and H₂O. The organic layer wasseparated and the aqueous layer was extracted with EtOAc (twice). Thecombined organic layer was washed with 1 M aqueous KHSO₄, saturatedaqueous NaHCO₃, and brine, dried over MgSO₄, filtered, concentrated, andpurified by flash chromatography (silica gel, 33% EtOAc in hexane) togive cis-(4-benzyloxycarbonylamino-cyclohexyl)-carbamic acid benzylester (52.0 g, 94%) as a colorless oil.

ESI MS m/e 405, M+Na⁺; ¹H NMR (300 MHz, CDCl₃) δ 7.15-7.40 (m, 10 H),5.07 (s, 4 H), 4.70-5.00 (m, 2 H), 3.52-3.80 (m, 2 H), 1.60-1.80 (m, 4H), 1.45-1.60 (m, 4 H).

Step B: Synthesis of cis-(4-amino-cyclohexyl)-carbamic acid tert-butylester.

To a solution of cis-(4-benzyloxycarbonylamino-cyclohexyl)-carbamic acidbenzyl ester (91.7 g, 240 mmol) in MeOH (460 mL) was added 5% Pd/C (9.17g). The reaction mixture was stirred at ambient temperature underhydrogen atmosphere for 2.5 days, filtered through a pad of celite, andconcentrated to give a diamine as a colorless oil. To a solution of thediamine in MeOH (550 mL) was added a solution of (Boc)₂O (6.59 g, 30.2mmol) in MeOH (80 mL) dropwise over 4 hr. The reaction mixture wasstirred at ambient temperature for 1.5 days and concentrated. Afterdissolution with H₂O, the aqueous layer was extracted with CHCl₃ (threetimes). The combined organic layer was dried over MgSO₄, filtered, andconcentrated to give cis-(4-amino-cyclohexyl)-carbamic acid tert-butylester (7.78 g, 15%, crude) as a colorless oil. The aqueous layer wasconcentrated and the residue was dissolved in MeOH, dried over MgSO₄,filtered, and concentrated to give a recovered diamine (32.9 g) as acolorless oil. To a solution of the recovered diamine (32.9 g, 288 mmol)in MeOH (660 mL) was added a solution of (Boc)₂O (6.29 g, 28.8 mmol) inMeOH (80 mL) dropwise over 5 hr. The reaction mixture was stirred atambient temperature for 10 hr and concentrated. After dissolution withH₂O, the aqueous layer was extracted with CHCl₃ (three times). Thecombined organic layer was dried over MgSO₄, filtered, and concentratedto give cis-(4-amino-cyclohexyl)-carbamic acid tert-butyl ester (8.16 g,16%, crude) as a colorless oil. The aqueous layer was concentrated andthe residue was dissolved in MeOH, dried over MgSO₄, filtered, andconcentrated to give a recovered diamine (23.1 g) as a colorless oil. Toa solution of the recovered diamine (23.1 g, 202 mmol) in MeOH (462 mL)was added a solution of (Boc)₂O (4.42 g, 20.3 mmol) in MeOH (56 mL)dropwise over 4 hr. The reaction mixture was stirred at ambienttemperature for 3.5 days and concentrated. After dissolution with H₂O,the aqueous layer was extracted with CHCl₃ (three times). The combinedorganic layer was dried over MgSO₄, filtered, and concentrated to givecis-(4-amino-cyclohexyl)-carbamic acid tert-butyl ester (5.01 g, 10%based on starting material) as a colorless oil. The aqueous layer wasconcentrated and the residue was dissolved in MeOH, dried over MgSO₄,filtered, and concentrated to give a recovered diamine (16.0 g) as acolorless oil. To a solution of the recovered diamine (16.0 g, 140 mmol)in MeOH (320 mL) was added a solution of (Boc)₂O (3.06 g, 14.0 mmol) inMeOH (40 mL) dropwise over 4 hr. The reaction mixture was stirred atambient temperature for 13 hr and concentrated. After dissolution withH₂O, the aqueous layer was extracted with CHCl₃ (three times). Thecombined organic layer was dried over MgSO₄, filtered, and concentratedto give cis-(4-amino-cyclohexyl)-carbamic acid tert-butyl ester (3.53 g,7% based on the starting material) as a colorless oil. The aqueous layerwas concentrated and the residue was dissolved in MeOH, dried overMgSO₄, filtered, and concentrated to give a recovered diamine (11.1 g)as a colorless oil.

ESI MS m/e 215, M+H⁺; ¹H NMR (300 MHz, CDCl₃) δ 4.30-4.82 (m, 1 H),3.50-3.80 (m, 1 H), 2.78-2.95 (m, 1 H), 1.44 (s, 9 H), 1.20-1.80 (m, 8H).

Step C: Synthesis ofcis-N²-(4-amino-cyclohexyl)-N⁴,N⁴-dimethyl-quinazoline-2,4-diamine.

A mixture of (2-chloro-quinazolin-4-yl)-dimethyl-amine obtained in stepB of example 1 (3.00 g, 14.4 mmol) and cis-(4-amino-cyclohexyl)-carbamicacid tert-butyl ester (3.72 g, 17.4 mmol) in 2-propanol (10 mL) wasstirred at reflux for 5.5 days, poured into saturated aqueous NaHCO₃,and the aqueous layer was extracted with CHCl₃ (three times). Thecombined organic layer was dried over MgSO₄, filtered, concentrated, andpurified by flash chromatography (NH-silica, 20% EtOAc in hexane) togive cis-[4-(4-dimethylamino-quinazolin-2-ylamino)-cyclohexyl]-carbamicacid tert-butyl ester including solvent (5.44 g) as a colorless oil. Toa solution of the above material (5.44 g) in EtOAc (10 mL) was added 4 Mhydrogen chloride in EtOAc (50 mL). The reaction mixture was stirred atambient temperature for 2 hr, and concentrated. The residue wasalkalized with saturated aqueous NaHCO₃, and the precipitate wascollected by filtration to givecis-N²-(4-amino-cyclohexyl)-N⁴,N⁴-dimethyl-quinazoline-2,4-diamine (2.26g, 55%) as a white solid. The aqueous layer was extracted CHCl₃ (threetimes). The combined organic layer was dried over MgSO₄, filtered, andconcentrated to givecis-N²-(4-amino-cyclohexyl)-N⁴,N⁴-diethyl-quinazoline-2,4-diamine (687mg, 17%) as a white solid.

ESI MS m/e 285, M; ¹H NMR (300 MHz, DMSO-d₆) δ 7.86 (d, J=7.5 Hz, 1 H),7.47 (t, J=8.3 Hz, 1 H), 7.29 (d, J=8.3 Hz, 1 H), 7.01 (t, J=7.6 Hz, 1H), 6.56 (d, J=7.5 Hz, 1 H), 3.83-4.06 (m, 1 H), 3.38-3.52 (m, 1 H),3.20 (s, 6 H), 1.22-1.82 (m, 8 H).

Step D: Synthesis ofcis-4-bromo-N-[4-(4-dimethylamino-quinazolin-2-ylamino)-cyclohexyl]-2-trifluoromethoxy-benzenesulfonamide.

To a suspension ofcis-N²-(4-amino-cyclohexyl)-N⁴,N⁴-dimethyl-quinazoline-2,4-diamine (680mg, 2.38 mmol) in CH₂Cl₂ (7 mL) was added diisopropylethylamine (620 μL,3.56 mmol). The mixture was cooled on an ice-bath and a solution of4-bromo-2-trifluoromethoxy-benzenesulfonyl chloride (849 mg, 2.50 mmol)in CH₂Cl₂ (3 mL) was added dropwise. The reaction mixture was stirred onan ice-bath for 6.5 hr. The reaction was quenched with saturated aqueousNaHCO₃ The aqueous layer was extracted with CHCl₃ (three times). Thecombined organic layer was dried over MgSO₄, filtered, concentrated, andpurified by flash chromatography (NH-silica gel, 33% EtOAc in hexane) togivecis-4-bromo-N-[4-(4-dimethylamino-quinazolin-2-ylamino)-cyclohexyl]-2-trifluoromethoxy-benzenesulfonamide(782 mg, 56%) as a pale yellow solid.

ESI MS m/e 588, M⁺; ¹H NMR (300 MHz, CDCl₃) δ 7.92 (d, J=8.9 Hz, 1 H),7.81 (dd, J=8.3, 1.2 Hz, 1 H), 7.41-7.58 (m, 4 H), 7.04 (ddd, J=8.3,6.6, 1.6 Hz, 1 H), 4.00-4.12 (m, 1 H), 3.36-3.45 (m, 1 H), 3.31 (s, 6H), 1.54-1.84 (m, 8 H).

Example 10

trans-N-{4-[(4-Dimethylamino-quinazolin-2-ylamino)-methyl]-cyclohexylmethyl}-methanesulfonamide

Step A: Synthesis oftrans-N-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-cyclohexylmethyl}-methanesulfonamide.

Using the procedure for the step H of example 1, the title compound wasobtained.

ESI MS m/e 392, M+H⁺; ¹H NMR (300 MHz, CDCl₃) δ 7.81 (d, J=7.8 Hz, 1 H),7.38-7.53 (m, 2 H), 7.02 (ddd, J=8.3, 6.6, 1.6 Hz, 1 H), 5.07 (brs, 1H), 4.61 (brs, 1 H), 3.36 (t, J=6.2 Hz, 2 H), 3.27 (s, 6 H), 2.94 (s, 3H), 2.91-3.01 (m, 2 H), 1.76-1.98 (m, 4 H), 1.37-1.64 (m, 2 H),0.85-1.12 (m, 4 H).

Example 11

trans-N-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-cyclohexylmethyl}-2-trifluoromethoxy-benzamide

Step A: Synthesis oftrans-N-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-cyclohexylmethyl}-2-trifluoromethoxy-benzamide.

To a suspension oftrans-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]cyclohexylmethyl}-carbamicacid tert-butyl ester obtained in step G of example 1 (800 mg, 1.93mmol) in EtOAc (10 mL) was added 4 M hydrogen chloride in EtOAc (10 mL).The mixture was stirred at ambient temperature for 60 min andconcentrated to give a white solid. To a suspension of the solid inCH₂Cl₂ (10 mL) was added diisopropylethylamine (706 μL, 4.05 mmol). Themixture was cooled at 4° C. and a solution of2-(trifluoromethoxy)benzoyl chloride (455 mg, 2.03 mmol) in CH₂Cl₂ (4mL) was added below 5° C. The reaction mixture was stirred at 4° C. for90 min. The reaction was quenched with saturated aqueous NaHCO₃ Theaqueous layer was extracted with CHCl₃ (three times). The combinedorganic layer was dried over MgSO₄, filtered, concentrated, and purifiedby flash chromatography (NH-silica gel, 33% EtOAc in hexane) to givetrans-N-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-cyclohexylmethyl}-2-trifluoromethoxy-benzamide(772 mg, 80%) as a pale yellow solid.

ESI MS m/e 502, M+H⁺; ¹H NMR (300 MHz, CDCl₃) δ 7.90 (dd, J=7.4, 1.6,Hz, 1 H), 7.81 (d, J=8.1 Hz, 1 H), 7.33-7.55 (m, 4 H), 7.29 (d, J=8.8,Hz, 1 H), 6.96-7.08 (m, 1 H), 6.55 (brs, 1 H), 4.97 (brs, 1 H),3.28-3.43 (m, 4 H), 3.26 (s, 6 H), 1.76-2.10 (m, 4 H), 1.44-1.72 (m, 2H), 0.90-1.21 (m, 4 H).

Example 12

trans-Butane-1-sulfonic acid{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-cyclohexylmethyl}-amide

Step A: Synthesis of trans-butane-1-sulfonic acid{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-cyclohexylmethyl}-amide.

Using the procedure for the step H of example 1, the title compound wasobtained.

ESI MS m/e 434, M+H⁺; ¹H NMR (300 MHz, CDCl₃) δ 7.81 (d, J=8.2 Hz, 1 H),7.35-7.54 (m, 2 H), 6.97-7.07 (m, 1 H), 4.41 (t, J=6.1 Hz, 1 H), 3.36(t, J=6.1 Hz, 2 H), 3.27 (s, 6 H), 2.89-3.05 (m, 4 H), 1.71-1.97 (m, 6H), 1.37-1.65 (m, 4 H), 0.82-1.12 (m, 7 H).

Example 13

trans-4-Bromo-N-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-cyclohexylmethyl}-2-trifluoromethoxy-benzamide

Step A: Synthesis of 4-bromo-2-trifluoromethoxy-benzaldehyde.

A solution of 4-bromo-1-iodo-2-trifluoromethoxy-benzene (1.00 g, 2.72mmol) in THF (15 mL) was cooled to −78° C., and 2.66 M BuLi in hexane(2.05 mL, 5.44 mmol) was added dropwise. The reaction mixture wasstirred at −78° C. for 1.5 h, and N-formylmorpholine (0.57 mL, 5.63mmol) was added. The reaction mixture was stirred at −78° C. for 15 minand at ambient temperature for 80 min. The reaction was quenched with0.25 M aqueous citric acid (10 mL), and the resulting mixture wasextracted with EtOAc (three times). The combined organic layer was driedover MgSO₄, filtered, concentrated, and purified by flash chromatography(silica gel, 2% to 5% EtOAc in hexane) to give4-bromo-2-trifluoromethoxy-benzaldehyde (560 mg, 77%) as a pale brownsolid.

CI MS m/e 269, M+H⁺; ¹H NMR (300 MHz, CDCl₃) δ 10.33 (s, 1 H), 7.85 (d,J=8.1 Hz, 1 H), 7.50-7.67 (m, 2 H).

Step B: Synthesis of 4-bromo-2-trifluoromethoxy-benzoic acid.

A solution of 4-bromo-2-trifluoromethoxy-benzaldehyde (550 mg, 2.04mmol) in 1,4-dioxane (27 mL) and H₂O (9 mL) was cooled at 4° C. To thesolution were added amidosulfuric acid (296 mg, 3.05 mmol) and sodiumdihydrogen phosphate dihydrate (1.4 g, 8.98 mmol). The mixture wasstirred at 4° C. for 15 min. To the reaction mixture was added asolution of sodium chlorite (238 mg, 2.63 mmol) in H₂O (1.5 mL) andstirred at 4° C. for 15 min. To the reaction mixture was added Na₂CO₃(304 mg, 2.41 mmol) and stirred at 4° C. for 15 min. The mixture wasacidified with conc-HCl (pH=1), and the aqueous layer was extracted withCHCl₃ (three times). The combined organic layer was dried over MgSO₄,filtered, concentrated, and purified by flash chromatography (silicagel, 1% MeOH in CHCl₃) to give 4-bromo-2-trifluoromethoxy-benzoic acid(471 mg, 81%) as a white solid.

ESI MS m/e 284, M^(+ ;) ¹H NMR (300 MHz, CDCl₃) δ 7.98 (d, J=8.4 Hz, 1H), 7.53-7.62 (m, 2 H).

Step C: Synthesis oftrans-4-bromo-N-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-cyclohexylmethyl}-2-trifluoromethoxy-benzamide.

To a solution of 4-bromo-2-trifluoromethoxy-benzoic acid (454 mg, 1.59mmol) in CH₂Cl₂ (6 mL) were added DMF (1.5 μL, 0.02 mmol) and SOCl₂ (158μL, 2.17 mmol). The mixture was stirred at reflux for 1 hr andconcentrated to give acid chloride as a pale yellow oil. To a suspensionoftrans-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]cyclohexylmethyl}-carbamicacid tert-butyl ester obtained in step G of example 1 (624 mg, 1.51mmol) in EtOAc (10 mL) was added 4 M hydrogen chloride in EtOAc (8 mL).The mixture was stirred at ambient temperature for 40 min andconcentrated to give a white solid. To a suspension of the solid inCH₂Cl₂ (6 mL) was added diisopropylethylamine (552 μL, 3.17 mmol). Themixture was cooled at 4° C. and a solution of acid chloride in CH₂Cl₂ (6mL) was added below 5° C. The reaction mixture was stirred at 4° C. for2.5 hr. The reaction was quenched with saturated aqueous NaHCO₃ Theaqueous layer was extracted with CHCl₃ (three times). The combinedorganic layer was dried over MgSO₄, filtered, concentrated, and purifiedby flash chromatography (NH-silica gel, 33% EtOAc in hexane) to givetrans-4-bromo-N-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-cyclohexylmethyl}-2-trifluoromethoxy-benzamide(309 mg, 35%) as a pale yellow solid.

ESI MS m/e 580, M+H⁺; ¹H NMR (300 MHz, CDCl₃) δ 7.89 (d, J=8.4 Hz, 1 H),7.81 (d, J=8.2 Hz, 1 H), 7.39-7.67 (m, 4 H), 7.02 (ddd, J=8.2, 6.4, 1.9Hz, 1 H), 6.53 (brs, 1 H), 4.99 (brs, 1 H), 3.37 (t, J=6.5 Hz, 2 H),3.32 (t, J=6.3 Hz, 2 H), 3.27 (s, 6 H), 1.76-2.02 (m, 4 H), 1.48-1.67(m, 2 H), 0.94-1.16 (m, 4 H).

Example 14

trans-N-{4-[(4-Dimethylamino-quinazolin-2-ylamino)-methyl]-cyclohexylmethyl}-2-trifluoromethoxy-benzenesulfonamide

Step A: Synthesis oftrans-N-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-cyclohexylmethyl}-2-trifluoromethoxy-benzenesulfonamide.

To a suspension oftrans-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]cyclohexylmethyl}-carbamicacid tert-butyl ester obtained in step G of example 1 (500 mg, 1.21mmol) in EtOAc (8 mL) was added 4 M hydrogen chloride in EtOAc (7 mL).The mixture was stirred at ambient temperature for 40 min andconcentrated to give a white solid. To a suspension of the solid inCH₂Cl₂ (7 mL) was added pyridine (215 μL, 2.66 mmol). The mixture wascooled at 4° C. and a solution of 2-trifluoromethoxy-benzenesulfonylchloride (331 mg, 1.27 mmol) in CH₂Cl₂ (2 mL) was added below 5° C. Thereaction mixture was stirred at 4° C. for 2 hr. The reaction wasquenched with saturated aqueous NaHCO₃ The aqueous layer was extractedwith CHCl₃ (three times). The combined organic layer was dried overMgSO₄, filtered, concentrated, and purified by flash chromatography(NH-silica gel, 20% EtOAc in hexane) to givetrans-N-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-cyclohexylmethyl}-2-trifluoromethoxy-benzenesulfonamide(231 mg, 36%) as a pale yellow solid.

ESI MS m/e 538, M+H⁺; ¹H NMR (300 MHz, CDCl₃) δ 8.03 (dd, J=8.0, 1.6 Hz,1 H), 7.81 (d, J=8.2 Hz, 1 H), 7.57-7.66 (m, 1 H), 7.36-7.52 (m, 4 H),7.02 (ddd, J=8.3, 6.5, 1.7 Hz, 1 H), 4.94 (brs, 1 H), 4.66 (brs, 1 H),3.34 (t, J=6.4 Hz, 2 H), 3.26 (s, 6 H), 2.78 (t, J=6.2 Hz, 2 H),1.68-2.01 (m, 4 H), 1.29-1.60 (m, 2 H), 0.79-1.07 (m, 4 H).

Example 15

trans-N²-{4-[(4-Bromo-2-trifluoromethoxy-benzylamino)-methyl]-cyclohexylmethyl}-N′,N-dimethyl-quinazoline-2,4-diamine

Step A: Synthesis oftrans-N⁴-(4-aminomethyl-cyclohexylmethyl)-N⁴,N⁴-dimethyl-quinazoline-2,4-diamine.

To a suspension oftrans-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-cyclohexylmethyl}-carbamicacid tert-butyl ester (20.1 g, 48.6 mmol) in EtOAc (200 mL) was added 4M hydrogen chloride in EtOAc (200 mL). The mixture was stirred atambient temperature for 90 min and concentrated to give a solid. Thesolid was alkalized with saturated aqueous NaHCO₃ (pH=9), concentrated,and purified by flash chromatography (NH silica gel, 33% MeOH in CHCl₃)to givetrans-N²-(4-aminomethyl-cyclohexylmethyl)-N⁴,N⁴-dimethyl-quinazoline-2,4-diamine(14.7 g, 97%) as a white solid.

ESI MS m/e 314, M+H⁺; ¹H NMR (300 MHz, CDCl₃) δ 7.81 (d, J=8.2 Hz, 1 H),7.42-7.52 (m, 2 H), 7.01 (ddd, J=8.2, 6.2, 0.9 Hz, 1 H), 4.95 (brs, 1H), 3.36 (t, J=6.3 Hz, 2 H), 3.26 (s, 6 H), 2.52 (d, J=6.4 Hz, 2 H),1.75-1.96 (m, 5 H), 1.48-1.66 (m, 1 H), 0.82-1.40(m, 6 H).

Step B: Synthesis oftrans-N²-{4-[(4-bromo-2-trifluoromethoxy-benzylamino)-methyl]-cyclohexylmethyl}-N⁴,N⁴-dimethyl-quinazoline-2,4-diamine.

To a solution oftrans-N²-(4-aminomethyl-cyclohexylmethyl)-N⁴,N⁴-dimethyl-quinazoline-2,4-diamine(500 mg, 1.59 mmol) in CH₂Cl₂ (5 mL) were added4-bromo-2-trifluoromethoxy-benzaldehyde obtained in step A of example 13(428 mg, 1.59 mmol), acetic acid (95 mg, 1.59 mmol), and NaBH(OAc)₃ (505mg, 2.38 mmol). The reaction mixture was stirred at ambient temperaturefor 4 hr. The reaction was quenched with saturated aqueous NaHCO₃. Theaqueous layer was extracted with CHCl₃ (three times). The combinedorganic layer was dried over MgSO₄, filtered, concentrated, and purifiedby flash chromatography (NH-silica gel, 50% EtOAc in hexane) to givetrans-N²-{4-[(4-bromo-2-trifluoromethoxy-benzylamino)-methyl]-cyclohexylmethyl}-N⁴,N⁴-dimethyl-quinazoline-2,4-diamine(783 mg, 89%) as a pale yellow solid.

ESI MS m/e 566, M+H⁺; ¹H NMR (300 MHz, CDCl₃) δ 7.80 (d, J=8.2 Hz, 1 H),7.34-7.52 (m, 5 H), 7.01 (ddd, J=8.3, 6.2, 2.0 Hz, 1 H), 5.00 (brs, 1H), 3.77 (s, 2 H), 3.36 (t, J=6.3 Hz, 2 H), 3.26 (s, 6 H), 2.43 (d,J=6.7 Hz, 2 H), 1.76-1.95 (m, 4 H), 1.34-1.65 (m, 2 H), 0.83-1.12(m, 4H).

Example 16

trans-4-Bromo-N-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-cyclohexylmethyl}-N-methyl-2-trifluoromethoxy-benzenesulfonamide

Step A: Synthesis oftrans-4-bromo-N-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-cyclohexylmethyl}-N-methyl-2-trifluoromethoxy-benzenesulfonamide.

To a solution oftrans-4-bromo-N-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-cyclohexylmethyl}-2-trifluoromethoxy-benzenesulfonamideobtained in step H of example 1 (380 mg, 0.61 mmol) in DMF (2 mL) wasadded 60% sodium hydride in oil (24.6 mg, 0.61 mmol). The reactionmixture was stirred at ambient temperature for 80 min. The reactionmixture was cooled at 0° C. and iodomethane (38.3 μL, 0.61 mmol) wasadded and stirred at ambient temperature for 3 hr. The reaction wasquenched with saturated aqueous NaHCO₃. The aqueous layer was extractedwith EtOAc (three times). The combined organic layer was dried overMgSO₄, filtered, concentrated, and purified by flash chromatography(NH-silica gel, 25% EtOAc in hexane, and silica gel, 5% MeOH in CHCl₃)to givetrans-4-bromo-N-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-cyclohexylmethyl}-N-methyl-2-trifluoromethoxy-benzenesulfonamide(268 mg, 69%) as a pale yellow solid.

ESI MS m/e 630, M+H⁺; ¹H NMR (300 MHz, CDCl₃) δ 7.88 (d, J=9.2 Hz, 1 H),7.81 (d, J=8.4 Hz, 1 H), 7.41-7.57 (m, 4 H), 7.03 (ddd, J=8.4, 6.3, 1.8Hz, 1 H), 3.37 (t, J=6.2 Hz, 2 H), 3.27 (s, 6 H), 2.97 (d, J=7.5 Hz,2H), 2.81 (s, 3H), 1.73-1.97 (m, 4H), 1.46-1.66 (m, 2H), 0.83-1.12 (m,4H).

Example 17

trans-N²-(4-{[(4-Bromo-2-trifluoromethoxy-benzyl)-methyl-amino]-methyl}-cyclohexylmethyl)-N⁴,N⁴-dimethyl-quinazoline-2,4-diamine

Step A: Synthesis oftrans-N²-(4-{[(4-bromo-2-trifluoromethoxy-benzyl)-methyl-amino]-methyl}-cyclohexylmethyl)-N⁴,N⁴-dimethyl-quinazoline-2,4-diamine.

To a solution oftrans-N²-{4-[(4-bromo-2-trifluoromethoxy-benzylamino)-methyl]-cyclohexylmethyl}-N⁴,N⁴-dimethyl-quinazoline-2,4-diamineobtained in step B of example 15 (290 mg, 0.52 mmol) in CH₂Cl₂ (3 mL)were added 37% aqueous formaldehyde (42 mg, 0.52 mmol), acetic acid (31mg, 0.52 mmol), and NaBH(OAc)₃ (165 mg, 0.78 mmol). The reaction mixturewas stirred at ambient temperature for 19 hr. The reaction was quenchedwith saturated aqueous NaHCO₃ The aqueous layer was extracted with CHCl₃(three times). The combined organic layer was dried over MgSO₄,filtered, concentrated, and purified by flash chromatography (NH-silicagel, 25% EtOAc in hexane) to givetrans-N²-(4-{[(4-bromo-2-trifluoromethoxy-benzyl)-methyl-amino]-methyl}-cyclohexylmethyl)-N⁴,N⁴-dimethyl-quinazoline-2,4-diamine(153 mg, 51%) as a pale yellow solid.

ESI MS m/e 580, M+H⁺; ¹H NMR (300 MHz, CDCl₃) δ 7.81 (d, J=7.6 Hz, 1 H),7.34-7.53 (m, 5 H), 7.02 (ddd, J=8.3, 6.2, 2.0 Hz, 1 H), 3.44 (s, 2 H),3.36 (t, J=6.3 Hz, 2 H), 3.27 (s, 6 H), 2.14 (s, 3 H), 2.11-2.18 (m, 2H), 1.81-1.96 (m, 4 H), 1.36-1.66 (m, 2 H), 0.73-1.13 (m, 4 H).

Example 18

trans-3-Trifluoromethoxy-biphenyl-4-sulfonic acid{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-cyclohexylmethyl}-amide

Step A: Synthesis of trans-3-trifluoromethoxy-biphenyl-4-sulfonic acid{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-cyclohexylmethyl}-amide.

To a solution oftrans-4-bromo-N-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-cyclohexylmethyl}-2-trifluoromethoxy-benzenesulfonamideobtained in step H of example 1 (122 mg, 0.198 mmol) in toluene (2.7 mL)were added MeOH (0.9 mL), 2 M aqueous K₂CO₃ (0.9 mL), phenylboronic acid(29.0 mg, 0.237 mmol), and tetrakis(triphenylphosphine)palladium (23.0mg, 0.02 mmol). The reaction mixture was stirred at 130° C. for 10 hr.The mixture was poured into water, and the aqueous layer was extractedwith CHCl₃ (three times). The combined organic layer was dried overMgSO₄, filtered, concentrated, and purified by flash chromatographyH-silica gel, 25% EtOAc in hexane and silica gel, 9% MeOH in CHCl₃) togive trans-3-trifluoromethoxy-biphenyl-4-sulfonic acid{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-cyclohexylmethyl}-amide(77 mg, 0.125 mmol) as a white solid.

ESI MS m/e 614, M+H⁺; ¹H NMR (200 MHz, CDCl₃) δ 8.07 (d, J=8.4 Hz, 1 H),7.82 (d, J=8.8 Hz, 1 H), 7.38-7.67 (m, 9 H), 7.03 (ddd, J=8.4, 6.2, 2.2Hz, 1 H), 5.11 (brs, 1 H), 4.71 (brs, 1 H), 3.35 (t, J=6.2 Hz, 2 H),3.27 (s, 6 H), 2.73-2.90 (m, 2 H), 1.67-2.03 (m, 4 H), 1.30-1.64 (m, 2H), 0.75-1.16 (m, 4 H).

Example 19

trans-Octane-1-sulfonicacid{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-cyclohexylmethyl}-amide

Step A: Synthesis of trans-octane-1-sulfonicacid{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-cyclohexylmethyl}-amide.

Using the procedure for the step H of example 1, the title compound wasobtained.

ESI MS m/e 490, M+H⁺; ¹H NMR (300 MHz, CDCl₃) δ 7.81 (d, J=7.8 Hz, 1 H),7.38-7.54 (m, 2 H), 7.02 (ddd, J=8.3, 6.6, 1.7 Hz, 1 H), 5.01 (brs, 1H), 4.45 (t, J=6.2 Hz, 1 H), 3.36 (t, J=6.2 Hz, 2 H), 3.26 (s, 6 H),2.86-3.04 (m, 4 H), 1.70-1.96 (m, 6 H), 1.12-1.65 (m, 11 H), 0.76-1.11(m, 8 H).

Example 20

trans-Propane-2-sulfonic acid{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-cyclohexylmethyl}-amide

Step A: Synthesis of trans-propane-2-sulfonic acid{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-cyclohexylmethyl}-amide.

To a suspension oftrans-N²-(4-aminomethyl-cyclohexylmethyl)-N⁴,N⁴-dimethyl-quinazoline-2,4-diamineobtained in step A of example 15 (227 mg, 0.72 mmol) in CH₂Cl₂ (4 mL)was added diisopropylethylamine (263 μL, 1.51 mmol). The mixture wascooled at 4° C. and a solution of 2-propanesulfonyl chloride (108 mg,0.76 mmol) in CH₂Cl₂ (1 mL) was added below 5° C. The reaction mixturewas stirred at ambient temperature for 12 hr. The reaction was quenchedwith saturated aqueous NaHCO₃ The aqueous layer was extracted with CHCl₃(three times). The combined organic layer was dried over MgSO₄,filtered, concentrated, and purified by flash chromatography (NH-silicagel, 66% EtOAc in hexane) to give trans-propane-2-sulfonic acid{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-cyclohexylmethyl}-amide(135 mg, 45%) as a pale yellow solid.

ESI MS m/e 420, M+H⁺; ¹H NMR (300 MHz, CDCl₃) δ 7.81 (d, J=7.8 Hz, 1 H),7.39-7.52 (m, 2 H), 7.02 (ddd, J=8.3, 6.5, 1.7 Hz, 1 H), 5.02 (brs, 1H), 4.22 (t, J=6.2 Hz, 1 H), 3.36 (t, J=6.2 Hz, 2 H), 3.27 (s, 6 H),3.09-3.21 (m, 1 H), 2.97 (t, J=6.5 Hz, 2 H), 1.75-1.97 (m, 4 H),1.39-1.64 (m, 2 H), 1.37 (d, J=6.8 Hz, 6 H), 0.85-1.12 (m, 4 H).

Example 21

N²-[1-(4-Bromo-2-trifluoromethoxy-benzenesulfonyl)-pyrrolidin-3-yl]-N⁴,N⁴-dimethyl-quinazoline-2,4-diamine

Step A: Synthesis of1-(4-bromo-2-trifluoromethoxy-benzenesulfonyl)-pyrrolidin-3-ylaminehydrochloride.

To a solution of pyrrolidin-3-yl-carbamic acid tert-butyl ester (1.00 g,5.37 mmol) in CH₂Cl₂ (10 mL) was added diisopropylethylamine (1.96 mL,5.92 mmol). The mixture was cooled at 0° C. and a solution of4-bromo-2-trifluoromethoxy-benzenesulfonyl chloride (2.01 g, 5.92 mmol)in CH₂Cl₂ (10 mL) was added below 10° C. The reaction mixture wasstirred at 4° C. for 15 min, dissolved in CHCl₃ and saturated aqueousNaHCO_(3.) The two phases were separated, the aqueous layer wasextracted with CHCl₃ (twice). The combined organic layer was dried overMgSO₄, filtered, concentrated, and dried under reduced pressure to givea pale brown solid. To a solution of the above solid in CHCl₃ (50 mL)was added 4 M hydrogen chloride in EtOAc (50 mL). The mixture wasstirred at ambient temperature for 1 hr, filtered, washed with EtOAc,and dried under reduced pressure to give1-(4-bromo-2-trifluoromethoxy-benzenesulfonyl)-pyrrolidin-3-ylaminehydrochloride (1.83 g, 80%) as a white solid.

ESI MS m/e 388, M⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 8.44 (brs, 3 H),7.82-7.94 (m, 3 H), 3.76-3.84 (m, 1 H), 3.42-3.58 (m, 2 H), 3.23-3.40(m, 2 H), 2.10-2.23 (m, 1 H), 1.88-2.02 (m, 1 H).

Step B: Synthesis ofN²-[1-(4-bromo-2-trifluoromethoxy-benzenesulfonyl)-pyrrolidin-3-yl]-N⁴,N⁴-dimethyl-quinazoline-2,4-diamine

Using the procedure for the step C of example 3, the title compound wasobtained.

ESI MS m/e 560, M+H⁺; ¹H NMR (300 MHz, CDCl₃) δ 7.82-7.89 (m, 2 H),7.40-7.75 (m, 4 H), 7.08 (ddd, J=8.3, 6.8, 1.5 Hz, 1 H), 4.83 (brs, 1H), 4.53-4.64 (m, 1 H), 3.75 (dd, J=10.3, 5.8 Hz, 1 H), 3.48-3.64 (m, 2H), 3.44 (dd, J=10.3, 4.4 Hz, 1 H), 3.27 (s, 6 H), 2.21-2.36 (m, 1 H),1.86-2.00 (m, 1 H).

Example 22

cis-4-Bromo-N-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-cyclohexylmethyl}-2-trifluoromethoxy-benzenesulfonamide

Step A: Synthesis ofcis-[4-(tert-butoxycarbonylamino-methyl)-cyclohexylmethyl]-carbamic acidtert-butyl ester.

To MeOH (220 mL) cooled at 0° C. was added thionyl chloride (52 mL)below 10° C. over 2.5 hr and the solution was stirred at 0° C. for 1 hr.To the reaction mixture was added cis-cyclohexane-1,4-dicarboxylic acid(30.0 g, 174 mmol) and the mixture was stirred at ambient temperaturefor 14 hr and concentrated. The residue was dissolved in CHCl₃, pouredinto saturated aqueous NaHCO₃, and the aqueous layer was extracted withCHCl₃ (three times). The combined organic layer was dried over MgSO₄,filtered, concentrated. A suspension of lithium aluminum hydride (13.2g, 348 mmol) in THF (400 mL) was cooled at −20° C. A solution of theabove residue in THF (200 mL) was added dropwise, and the mixture wasstirred at ambient temperature for 3 hr. The reaction was quenched withNa₂SO₄.10H₂O, filtered through a pad of celite, and concentrated. To asolution of the above residue in toluene (500 mL) was addedtriphenylphosphine (37.2 g, 142 mmol). To the mixture cooled at 4° C.were added phthalimide (20.9 g, 142 mmol) and 40% diethylazodicarboxylate (DEAD) in toluene (61.7 mL, 136 mmol) over 25 min. Thereaction mixture was stirred at ambient temperature for 12 hr, pouredinto H₂O. The aqueous layer was extracted with CHCl₃ (three times). Thecombined organic layer was dried over MgSO₄, filtered, concentrated. Theprecipitate was suspended in Et₂O, filtered, washed with MeOH and Et₂O,and dried under reduced pressure to give a white solid (16.5 g). To asuspension of the above solid (16.5 g, 410 mmol) in EtOH (735 mL) wasadded hydrazine hydrate (20.5 g, 410 mmol). The mixture was stirred atreflux for 2.5 hr, cooled, and concentrated. The precipitate wasdissolved in 10% aqueous sodium hydroxide (120 mL) and 1,4-dioxane (160mL). To the mixture cooled on an ice-bath was added (Boc)₂O (30.4 g, 139mmol) and the mixture was stirred at ambient temperature for 2.5 hr, andpoured into H₂O. The aqueous layer was extracted with CHCl₃ (ten times).The combined organic layer was dried over MgSO₄, filtered andconcentrated. The precipitate was suspended in hexane, filtered, washedwith hexane, and dried under reduced pressure to givecis-[4-(tert-butoxycarbonylamino-methyl)-cyclohexylmethyl]-carbamic acidtert-butyl ester (5.10 g, 9%) as a white solid.

ESI MS m/e 365, M+Na⁺; ¹H NMR (300 MHz, CDCl₃) δ 4.49-4.59 (m, 2 H),3.05 (t, J=6.6 Hz, 4 H), 1.29-1.69 (m, 28 H).

Step C: Synthesis of cis-(4-aminomethyl-cyclohexylmethyl)-carbamic acidtert-butyl ester.

To a solution ofcis-[4-(tert-butoxycarbonylamino-methyl)-cyclohexylmethyl]-carbamic acidtert-butyl ester (2.55 g, 7.45 mmol) in CH₂Cl₂ (40 mL) was added 4 Mhydrogen chloride in EtOAc (4 mL). The reaction mixture was stirred atambient temperature for 5 hr and concentrated. The residue was dissolvedin 1,4-dioxane (20 mL) and 10% aqueous sodium hydroxide (40 mL) and theresulting solution was cooled on an ice-bath. (Boc)₂O (829 mg, 3.80mmol) was added dropwise and the mixture was stirred at ambienttemperature for 3 h. The aqueous layer was extracted with CHCl₃ (threetimes). The combined organic layer was dried over MgSO₄, filtered andconcentrated, and purified by flash chromatography (silica gel, 9% MeOHin CHCl₃) to give cis-(4-aminomethyl-cyclohexylmethyl)-carbamic acidtert-butyl ester (255 mg, 14%) as a pale yellow oil.

ESI MS m/e 243, M+H⁺; ¹H NMR (300 MHz, CDCl₃) δ 4.58 (brs, 1 H), 3.06(t, J=6.7 Hz, 2 H), 2.60 (d, J=5.9 Hz, 2 H), 1.28-1.70 (m, 19 H).

Step D: Synthesis ofcis-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-cyclohexylmethyl}-carbamicacid tert-butyl ester.

Using the procedure for the step G of example 1, the title compound wasobtained.

ESI MS m/e 414, M+H⁺; ¹H NMR (300 MHz, CDCl₃) δ 7.81 (d, J=7.8 Hz, 1 H),7.42-7.52 (m, 2 H), 7.02 (ddd, J=8.3, 6.3, 1.9 Hz, 1 H), 4.52 (brs, 1H), 3.45 (t, J=6.6 Hz, 2 H), 3.27 (s, 6 H), 3.08 (t, J=6.5 Hz, 2 H),1.34-1.86 (m, 19 H).

Step E: Synthesis ofcis-4-bromo-N-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-cyclohexylmethyl}-2-trifluoromethoxy-benzenesulfonamide.

Using the procedure for the step H of example 1, the title compound wasobtained.

ESI MS m/e 616, M+H⁺; ¹H NMR (300 MHz, CDCl₃) δ 7.90 (d, J=8.9 Hz, 1 H),7.81 (d, J=7.8 Hz, 1 H), 7.41-7.58 (m, 4 H), 7.03 (ddd, J=8.2, 6.6, 1.5Hz, 1 H), 3.41 (t, J=6.5 Hz, 2-H), 3.50 (s, 6 H), 2.90 (d, J=7.3 Hz, 2H), 1.32-1.86 (m, 10 H).

Example 23

cis-4-Bromo-N-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-cyclohexyl}-2-trifluoromethoxy-benzenesulfonamide

Step A: Synthesis of cis-(4-hydroxymethyl-cyclohexyl)-carbamic acidtert-butyl ester.

A suspension of cis-4-amino-cyclohexanecarboxylic acid (244 g, 1.70 mol)in MeOH (2.45 L) was cooled to −8° C. Thionyl chloride (45.0 mL, 617mmol) was added dropwise. The resulting solution was stirred at ambienttemperature for 4.5 hr and concentrated to give a white solid. To asuspension of the above solid in CHCl₃ (3.00 L) were added triethylamine(261 mL, 1.87 mol) and (Boc)₂O (409 g, 1.87 mol) successively. Thereaction mixture was stirred at ambient temperature for 5 hr and pouredinto water. The aqueous layer was extracted with CHCl₃ (three times).The combined organic layer was dried over MgSO₄, filtered, concentrated,and purified by flash chromatography (silica gel, CHCl₃ only to 10% MeOHin CHCl₃) to give a colorless oil (531 g). To a suspension cooled at −4°C. of lithium aluminum hydride (78.3 g, 2.06 mol) in Et₂O (7.9 L) wasadded a solution of above oil (530.9 g) in Et₂O (5.3 L) below 0° C. Theresulting suspension was stirred at ambient temperature for 2 hr. Thereaction mixture was cooled on an ice-bath, quenched with cold water,filtered through a pad of celite. The filtrate was dried over MgSO₄,filtered, and concentrated. The precipitate was suspended in hexane (300mL), filtered, washed with hexane, and dried under reduced pressure togive cis-(4-hydroxymethyl-cyclohexyl)-carbamic acid tert-butyl ester(301 g, 77%) as a white solid.

ESI MS m/e 252, M+Na⁺; ¹H NMR (300 MHz, CDCl₃) δ 4.30-4.82 (m, 1 H),3.75 (brs, 1 H), 3.51 (d, J=6.2 Hz, 1 H), 1.52-1.77 (m, 7 H), 1.45 (s, 9H), 1.16-1.36 (m, 2 H).

Step B: Synthesis ofcis-[4-(benzyloxycarbonylamino-methyl)-cyclohexyl]-carbamic acidtert-butyl ester.

To a solution of cis-(4-hydroxymethyl-cyclohexyl)-carbamic acidtert-butyl ester (17.7 g, 77.2 mmol) in THF (245 mL) were addedtriphenylphosphine (20.2 g, 77.0 mmol) and phthalimide (11.4 g, 77.5mmol) successively. The resulting suspension was cooled on an ice-bathand 40% diethyl azodicarboxylate (DEAD) in toluene was added over 1 hr.The reaction mixture was stirred at ambient temperature for 2.5 days,concentrated, and purified by flash chromatography (silica gel, 33%EtOAc in hexane) to give a white solid. To a suspension of above solid(27.5 g) in EtOH (275 mL) was added hydrazine hydrate (5.76 g, 115mmol). The mixture was stirred at reflux for 2.25 hr, cooled,concentrated. The precipitate was dissolved in 10% aqueous sodiumhydroxide (350 mL). The aqueous layer was extracted with CHCl₃ (threetimes). The combined organic layer was dried over MgSO₄, filtered andconcentrated. To a solution of the above residue in CHCl₃ (275 mL) wasadded triethylamine (8.54 g, 84.4 mmol). The resulting solution wascooled to 0° C. and ZCl (14.4 g, 84.4 mmol) was added below 5° C. Thereaction mixture was stirred at ambient temperature for 16 hr, andpoured into saturated aqueous NaHCO₃. The aqueous layer was extractedwith CHCl₃ (three times). The combined organic layer was dried overMgSO₄, filtered, concentrated, and purified by flash chromatography(silica gel, 2% MeOH in CHCl₃) to givecis-[4-(benzyloxycarbonylamino-methyl)-cyclohexyl]-carbamic acidtert-butyl ester (25.3 g, 91%) as a colorless oil.

ESI MS m/e 385, M+Na⁺; ¹H NMR (300 MHz, CDCl₃) δ 7.27-7.38 (m, 5 H),5.09 (s, 2 H), 4.76-4.92 (m, 1 H), 4.42-4.76 (m, 1 H), 3.72 (brs, 1 H),3.10 (t, J=6.4 Hz, 2 H), 1.48-1.75 (m, 7 H), 1.44 (s, 9 H), 1.13-1.31(m, 2 H).

Step C: Synthesis ofcis-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-cyclohexyl}-carbamicacid tert-butyl ester.

A mixture of cis-[4-(benzyloxycarbonylamino-methyl)-cyclohexyl]-carbamicacid tert-butyl ester (4.00 g, 11.0 mmol) and 5% Pd/C (400 mg) in MeOH(40 mL) was stirred under hydrogen atmosphere at ambient temperature for8.5 hr and at 50° C. for 12 hr, filtered through a pad of celite, andconcentrated. The precipitate was suspended in hexane and the suspensionwas stirred at ambient temperature for 30 min. The solid was collectedby filtration, washed with hexane, and dried (3.03 g). A mixture of(2-chloro-quinazolin-4-yl)-dimethyl-amine obtained in step B of example1 (1.00 g, 4.82 mmol) and the above solid (1.65 g, 7.23 mmol) in2-propanol (10 mL) was stirred at reflux for 5 days, poured intosaturated aqueous NaHCO₃, and the aqueous layer was extracted with CHCl₃(three times). The combined organic layer was dried over MgSO₄,filtered, concentrated, and purified by flash chromatography (NH-silicagel, 20% EtOAc in hexane) to givecis-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-cyclohexyl}-carbamicacid tert-butyl ester (629 mg, 43%) as a pale yellow solid.

ESI MS m/e 400, M+H⁺; ¹H NMR (300 MHz, CDCl₃) δ 7.81 (d, J=8.2 Hz, 1 H),7.42-7.56 (m, 2 H), 6.98-7.06 (m, 1 H), 4.64-4.75 (m, 1 H), 3.67-3.82(m, 1 H), 3.29-3.44 (m, 2 H), 3.28 (s, 6 H), 1.50-1.78 (m, 7 H), 1.45(s, 9 H), 1.21-1.42 (m, 2 H).

Step D: Synthesis ofcis-4-bromo-N-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-cyclohexyl}-2-trifluoromethoxy-benzenesulfonamid.

Using the procedure for the step H of example 1, the title compound wasobtained.

ESI MS m/e 602, M+H⁺; ¹H NMR (300 MHz, CDCl₃) δ 7.91 (d, J=8.9 Hz, 1 H),7.82 (dd, J=8.0, 1.0 Hz, 1 H), 7.42-7.56 (m, 4 H), 7.04 (ddd, J=8.3,6.6, 1.6 Hz, 1 H), 3.44-3.50 (m, 1 H), 3.40 (t, J=6.0 Hz, 2 H), 3.28 (s,6 H), 1.22-1.78 (m, 9 H).

Example 24

cis-4-Bromo-N-[4-(4-dimethylamino-quinazolin-2-ylamino)-cyclohexylmethyl]-2-trifluoromethoxy-benzenesulfonamide

Step A: Synthesis of cis-(4-amino-cyclohexylmethyl)-carbamic acid benzylester.

To a solution ofcis-[4-(benzyloxycarbonylamino-methyl)-cyclohexyl]-carbamic acidtert-butyl ester obtained in step C of example 23 (12.9 g, 35.6 mmol) inEtOAc (129 mL) was added 4 M hydrogen chloride in EtOAc (129 mL). Thereaction mixture was stirred at ambient temperature for 3 hr, filtered,washed with EtOAc, and dried under reduced pressure. The solid wasdissolved in saturated aqueous NaHCO₃. The aqueous layer was extractedwith CHCl₃ (five times), dried over MgSO₄, filtered and concentrated,and dried under reduced pressure to givecis-(4-amino-cyclohexylmethyl)-carbamic acid benzyl ester (8.88 g, 95%)as a colorless oil.

ESI MS m/e 263, M+H⁺; ¹H NMR (300 MHz, CDCl₃) δ 7.36 (s, 5 H), 5.12(brs, 3 H), 2.96-3.32 (m, 3 H), 1.36-1.98 (m, 9 H).

Step B: Synthesis ofcis-[4-(4-dimethylamino-quinazolin-2-ylamino)-cyclohexylmethyl]-carbamicacid benzyl ester.

Using the procedure for the step G of example 1, the title compound wasobtained.

ESI MS m/e 434, M+H⁺; ¹H NMR (300 MHz, CDCl₃) δ 7.81 (d, J=9.0 Hz, 1 H),7.26-7.52 (m, 7 H), 7.01 (ddd, J=8.2, 6.5, 1.7 Hz, 1 H), 5.10 (s, 2 H),4.93-5.06 (m, 1 H), 4.82-4.93 (m, 1 H), 4.18-4.28 (m, 1 H), 3.26 (s, 6H), 3.11 (t, J=6.3 Hz, 2 H), 1.80-1.93 (m, 2 H), 1.52-1.73 (m, 5 H),1.23-1.40 (m, 2 H).

Step C: Synthesis ofcis-4-bromo-N-[4-(4-dimethylamino-quinazolin-2-ylamino)-cyclohexylmethyl]-2-trifluoromethoxy-benzenesulfonamide.

Using the procedure for the step D of example 3, the title compound wasobtained.

ESI MS m/e 602, M+H⁺; ¹H NMR (300 MHz, CDCl₃) δ 7.90 (d, J=8.9 Hz, 1 H),7.81 (dd, J=8.3, 1.3 Hz, 1 H), 7.38-7.59 (m, 4 H), 7.02 (ddd, J=8.2,6.8, 1.2 Hz, 1 H), 4.75-5.24 (m, 1 H), 4.16-4.27 (m, 1 H), 3.27 (s, 6H), 2.86 (d, J=6.4 Hz, 2 H), 1.78-1.91 (m, 2 H), 1.51-1.70 (m, 5 H),1.21-1.38 (m, 2 H).

Example 25

4-Bromo-N-[1-(4-dimethylamino-quinazolin-2-yl)-pyrrolidin-3-yl]-2-trifluoromethoxy-benzenesulfonamide

Step A: Synthesis of[1-(4-dimethylamino-quinazolin-2-yl)-pyrrolidin-3-yl]-carbamic acidtert-butyl ester.

Using the procedure for the step G of example 1, the title compound wasobtained.

ESI MS m/e 358, M+H⁺; ¹H NMR (300 MHz, CDCl₃) δ 7.81 (d, J=8.2 Hz, 1 H),7.45-7.54 (m, 2 H), 6.98-7.05 (m, 1 H), 4.67-4.80 (m, 1 H), 4.25-4.40(m, 1 H), 3.85-3.94 (m, 1 H), 3.68-3.79 (m, 2 H), 3.52-3.62 (m, 1 H),3.27 (s, 6 H), 2.16-2.28 (m, 1 H), 1.86-2.01 (m, 1 H), 1.45(s, 9 H).

Step B: Synthesis of4-bromo-N-[1-(4-dimethylamino-quinazolin-2-yl)-pyrrolidin-3-yl]-2-trifluoromethoxy-benzenesulfonamide.

Using the procedure for the step H of example 1, the title compound wasobtained.

ESI MS m/e 560, M+H⁺; ¹H NMR (300 MHz, CDCl₃) δ 7.94 (d, J=8.4 Hz, 1 H),7.81 (d, J=8.1 Hz, 1 H), 7.44-7.58 (m, 4 H), 7.03 (ddd, J=8.4, 5.7, 2.6Hz, 1 H), 4.76-5.04 (m, 1 H), 3.96-4.11 (m, 1 H), 3.70-3.82 (m, 2 H),3.58-3.68 (m, 1 H), 3.45-3.54 (m, 1 H), 3.25 (s, 6 H), 2.11-2.24 (m, 1H), 1.86-1.99 (m, 1 H).

Example 26

4-Bromo-N-[4-(4-dimethylamino-quinazolin-2-ylamino)-benzyl]-2-trifluoromethoxy-benzenesulfonamide

Step A: Synthesis of (4-amino-benzyl)-carbamic acid tert-butyl ester.

To a solution of 4-aminomethyl-phenylamine (1.00 g, 8.19 mmol) in CHCl₃(10 mL) was added triethylamine (870 mg, 8.60 mmol). After cooling on anice-bath, (Boc)₂O (1.88 g, 8.61 mmol) was added dropwise. The reactionmixture was stirred at ambient temperature for 55 min and poured intosaturated aqueous NaHCO₃. The aqueous layer was extracted with CHCl₃(three times). The combined organic layer was dried over MgSO₄,filtered, concentrated, and purified by flash chromatography (silicagel, 9% MeOH in CHCl₃) to give (4-amino-benzyl)-carbamic acid tert-butylester (1.79 g, 99%) as a yellow solid.

ESI MS m/e 245, M+Na⁺; ¹H NMR (200 MHz, CDCl₃) δ 7.07 (d, J=8.4 Hz, 2H), 6.63 (d, J=8.4 Hz, 2 H), 4.76 (brs, 1 H), 4.18 (d, J=5.3 Hz, 2 H),3.65 (brs, 2 H), 1.45 (s, 9 H).

Step B: Synthesis of4-bromo-N-[4-(4-dimethylamino-quinazolin-2-ylamino)-benzyl]-2-trifluoromethoxy-benzenesulfonamide.

A mixture of (2-chloro-quinazolin-4-yl)-dimethyl-amine obtained in stepB of example 1 (1.00 g, 4.82 mmol) and (4-amino-benzyl)-carbamic acidtert-butyl ester (1.28 g, 5.76 mmol) in 2-propanol (10 mL) was stirredat reflux for 3 hr, cooled, poured into saturated aqueous NaHCO₃, andthe aqueous layer was extracted with CHCl₃ (three times). The combinedorganic layer was dried over MgSO₄, filtered, concentrated, and purifiedby flash chromatography (NH-silica gel, 20% EtOAc in hexane) to give apale yellow solid (2.32 g). To a solution of the above solid (750 mg,1.91 mmol) in EtOAc (7 mL) was added 4 M hydrogen chloride in EtOAc (7mL). The mixture was stirred at ambient temperature for 2 hr,concentrated to give a white solid. To a suspension of the above solidin CH₂Cl₂ (5 mL) was added diisopropylethylamine (730 μL, 4.19 mmol).The mixture was cooled on an ice-bath and a solution of4-bromo-2-trifluoromethoxy-benzenesulfonyl chloride (777 mg, 2.29 mmol)in CH₂Cl₂ (2 mL) was added dropwise. The reaction mixture was stirred onan ice-bath for 9 hr, poured into saturated aqueous NaHCO₃. The aqueouslayer was extracted with CHCl₃ (three times). The combined organic layerwas dried over MgSO₄, filtered, concentrated, and purified bymedium-pressure liquid chromatography (NH-silica gel, 20% EtOAc inhexane) to give4-bromo-N-[4-(4-dimethylamino-quinazolin-2-ylamino)-benzyl]-2-trifluoromethoxy-benzenesulfonamide(519 mg, 56%) as a pale yellow solid.

ESI MS m/e 618, M+Na⁺; ¹H NMR (300 MHz, CDCl₃) δ 7.88 (t, J=9.0 Hz, 2H), 7.64 (d, J=8.6 Hz, 2 H), 7.48-7.61 (m, 4 H), 6.98-7.20 (m, 4 H),4.96 (brs, 1 H), 4.13 (s, 2 H), 3.34 (s, 6 H).

Example 27

4-Bromo-N-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-benzyl}-2-trifluoromethoxy-benzenesulfonamide

Step A: Synthesis of (4-aminomethyl-benzyl)-carbamic acid tert-butylester.

To a solution of 4-aminomethyl-benzylamine (15.0 g, 110 mmol) in CHCl₃(85 mL) was added a solution of (Boc)₂O (3.03 g, 13.9 mmol) in CHCl₃ (45mL) dropwise over 3.5 hr. The reaction mixture was stirred at ambienttemperature for 13 hr, and concentrated. After dissolution with H₂O, theaqueous layer was extracted with EtOAc (three times). The combinedorganic layer was washed with H₂O (three times), dried over MgSO₄,filtered, and concentrated to give (4-aminomethyl-benzyl)-carbamic acidtert-butyl ester (3.20 g, 12%) as a white solid.

ESI MS m/e 237, M+H⁺; ¹H NMR (300 MHz, CDCl₃) δ 7.21-7.30 (m, 4 H),4.86-5.02 (m, 1 H), 4.29 (d, J=5.8 Hz, 2 H), 3.84 (s, 2 H), 1.46 (s, 9H).

Step B: Synthesis of{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-benzyl}-carbamic acidtert-butyl ester.

Using the procedure for the step G of example 1, the title compound wasobtained.

ESI MS m/e 408, M+H⁺; ¹H NMR (300 MHz, CDCl₃) δ 7.85 (d, J=8.2 Hz, 1 H),7.47-7.55 (m, 2 H), 7.37 (d, J=8.0 Hz, 2 H), 7.24 (d, J=8.0 Hz, 2 H),7.05-7.10 (m, 1 H), 5.35-5.45 (m, 1 H), 4.90-5.04 (m, 1 H), 4.72 (d,J=5.8 Hz, 2 H), 4.31 (d, J=5.8 Hz, 2 H), 3.27 (s, 6 H), 1.49 (s, 9 H).

Step C: Synthesis of4-bromo-N-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-benzyl}-2-trifluoromethoxy-benzenesulfonamide.

Using the procedure for the step H of example 1, the title compound wasobtained.

ESI MS m/e 610, M+H⁺; ¹H NMR (300 MHz, CDCl₃) δ 7.83 (d, J=8.4 Hz, 2 H),7.44-7.54 (m, 4 H), 7.29 (d, J=7.9 Hz, 2 H), 7.11 (d, J=8.1 Hz, 2 H),7.06 (ddd, J=8.3, 6.3, 2.0 Hz, 1 H), 4.67 (d, J=5.9 Hz, 2 H), 4.15 (s, 2H), 3.26 (s, 6 H).

Example 28

cis-N²-[4-(4-Bromo-2-trifluoromethoxy-benzylamino)-cyclohexyl]-N⁴,N⁴-dimethyl-quinazoline-2,4-diamine

Step A: Synthesis ofcis-N²-[4-(4-bromo-2-trifluoromethoxy-benzylamino)-cyclohexyl]-N⁴,N⁴-dimethyl-quinazoline-2,4-diamine.

Using the procedure for the step B of example 15, the title compound wasobtained.

ESI MS m/e 560, M+Na⁺; ¹H NMR (300 MHz, CDCl₃) δ 7.80 (dd, J=7.9, 0.9Hz, 1 H), 7.36-7.51 (m, 5 H), 7.01 (ddd, J=8.3, 6.4, 1.9 Hz, 1 H),4.95-5.18 (m, 1 H), 4.08-4.22 (m, 1 H), 3.81 (s, 2 H), 3.25 (s, 6 H),2.55-2.70 (m, 1 H), 1.65-1.90 (m, 6 H), 1.29-1.65 (m, 2 H).

Example 29

cis-N-[4-(4-Dimethylamino-quinazolin-2-ylamino)-cyclohexyl]-2-trifluoromethoxy-benzenesulfonamide

Step A: Synthesis ofcis-N-[4-(4-dimethylamino-quinazolin-2-ylamino)-cyclohexyl]-2-trifluoromethoxy-benzenesulfonamide.

Using the procedure for the step A of example 20, the title compound wasobtained.

ESI MS m/e 532, M+Na⁺; ¹H NMR (300 MHz, CDCl₃) δ 8.06 (dd, J=8.1, 1.9Hz, 1 H), 7.81 (dd, J=8.4, 1.4 Hz, 1 H), 7.36-7.66 (m, 5 H), 7.03 (ddd,J=8.3, 6.7, 1.5 Hz, 1 H), 4.72-5.07 (m, 2 H), 3.95-4.10 (m, 1 H),3.32-3.48 (m, 1 H), 3.25 (s, 6 H), 1.37-2.17 (m, 8 H).

Example 30

N²-[1-(4-Bromo-2-trifluoromethoxy-benzyl)-piperidin-4-yl]-N⁴,N⁴-dimethyl-quinazoline-2,4-diamine

Step A: Synthesis ofIV-(1-benzyl-piperidin-4-yl)-N⁴,N⁴-dimethyl-quinazoline-2,4-diamine.

Using the procedure for the step G of example 1, the title compound wasobtained.

ESI MS m/e 362, M+H⁺; ¹H NMR (300 MHz, CDCl₃) δ 7.80 (d, J=7.6 Hz, 1 H),7.20-7.52 (m, 7 H), 6.97-7.05 (m, 1 H), 4.74-4.90 (m, 1 H), 3.90-4.05(m, 1 H), 3.53 (s, 2 H), 3.26 (s, 6 H), 2.78-2.90 (m, 2 H), 2.02-2.24(m, 4 H), 1.48-1.62 (m, 2 H).

Step B: Synthesis ofN⁴,N⁴-dimethyl-N²-piperidin-4-yl-quinazoline-2,4-diamine.

To a solution ofN²-(1-benzyl-piperidin-4-yl)-N⁴,N⁴-dimethyl-quinazoline-2,4-diamine(1.80 g, 4.98 mmol) in MeOH (18 mL) was added 20% Pd(OH)₂ (360 mg). Themixture was stiffed at 50° C. under hydrogen atmosphere for 3 days,filtered through a pad of celite, and concentrated to giveN⁴,N⁴-dimethyl-N²-piperidin-4-yl-quinazoline-2,4-diamine (1.33 g, 99%)as a pale yellow solid.

ESI MS m/e 272, M+H⁺; ¹H NMR (300 MHz, CDCl₃) δ 7.86 (d, J=8.6 Hz, 1 H),7.43-7.62 (m, 2 H), 7.15 (t, J=8.2 Hz, 1 H), 4.12-4.29 (m, 1 H),3.29-3.47 (m, 2 H), 3.37 (s, 6 H), 2.96-3.12 (m, 2 H), 2.20-2.34 (m, 2H), 1.79-1.97 (m, 2 H).

Step C: Synthesis ofIV-[1-(4-bromo-2-trifluoromethoxy-benzyl)-piperidin-4-yl-]N⁴,N⁴-dimethyl-quinazoline-2,4-diamine.

Using the procedure for the step B of example 15, the title compound wasobtained.

ESI MS m/e 546, M+Na⁺; ¹H NMR (300 MHz, CDCl₃) δ 7.80 (dd, J=8.7, 0.9Hz, 1 H), 7.34-7.54 (m, 5 H), 7.01 (ddd, J=8.3, 6.6, 1.6 Hz, 1 H),4.76-4.95 (m, 1 H), 3.87-4.06 (m, 1 H), 3.52 (s, 2 H), 3.25 (s, 6 H),2.71-2.86 (m, 2 H), 2.17-2.33 (m, 2 H), 1.97-2.12 (m, 2 H), 1.44-1.61(m, 2 H).

Example 31

N⁴,N⁴-Dimethyl-N⁴-[1-(2-trifluoromethoxy-benzenesulfonyl)-piperidin-4-yl]-quinazoline-2,4-diamine

Step A: Synthesis ofN⁴,N⁴-dimethyl-N²-[1-(2-trifluoromethoxy-benzenesulfonyl)-piperidin-4-yl]-quinazoline-2,4-diamine.

Using the procedure for the step A of example 20, the title compound wasobtained.

ESI MS m/e 518, M+Na⁺; ¹H NMR (300 MHz, CDCl₃) δ 8.02 (dd, J=7.9, 1.9Hz, 1 H), 7.81 (dd, J=8.4, 0.7 Hz, 1 H), 7.34-7.67 (m, 5 H), 7.04 (ddd,J=8.3, 6.7, 1.5 Hz, 1 H), 4.81 (brs, 1 H), 3.95-4.12 (m, 1 H), 3.78 (d,J=12.8 Hz, 2 H), 3.25 (s, 6 H), 2.85-3.05 (m, 2 H), 2.05-2.28 (m, 2 H),1.50-1.71 (m, 2 H).

Example 32

4-Bromo-N-[4-(4-dimethylamino-quinazolin-2-ylamino)-phenyl]-2-trifluoromethoxy-benzenesulfonamide

Step A: Synthesis of[4-(4-dimethylamino-quinazolin-2-ylamino)-phenyl]-carbamic acidtert-butyl ester.

Using the procedure for the step G of example 1, the title compound wasobtained.

ESI MS m/e 402, M+Na⁺; ¹H NMR (300 MHz, CDCl₃) δ 10.05 (brs, 1 H), 7.94(d, J=8.4 Hz, 1 H), 7.50-7.66 (m, 4 H), 7.23-7.38 (m, 3 H), 6.57-6.64(m, 1 H), 3.48 (s, 6 H), 1.53 (s, 9 H).

Step B: Synthesis of4-bromo-N-[4-(4-dimethylamino-quinazolin-2-ylamino)-phenyl]-2-trifluoromethoxy-benzenesulfonamide

To a suspension of[4-(4-dimethylamino-quinazolin-2-ylamino)-phenyl]-carbamic acidtert-butyl ester (380 mg, 1.00 mmol) in EtOAc (4 mL) and CH₂Cl₂ (4 mL)was added 4 M hydrogen chloride in EtOAc (4 mL). The mixture was stirredat ambient temperature for 4 hr and concentrated to give a white solid.The solid was alkalized with saturated aqueous NaHCO₃ filtered, washedwith H₂O and hexane, and dried at 50° C. under reduced pressure. To asolution of 4-bromo-2-trifluoromethoxy-benzenesulfonyl chloride (680 mg,2.00 mmol) in CH₂Cl₂ (30 mL) was added PVP (8 mL). To the resultingsuspension was added a solution of the above solid in CH₂Cl₂ (5 mL). Themixture was stirred at ambient temperature for 10.5 hr and filtered. Thefiltrate was washed with saturated aqueous NaHCO₃, dried over MgSO₄,filtered, concentrated, and purified by medium-pressure liquidchromatography (NH-silica gel, EtOAc) to give a solid. The solid waswashed with Et₂O and dried at 50° C. under reduced pressure to give4-bromo-N-[4-(4-dimethylamino-quinazolin-2-ylamino)-phenyl]-2-trifluoromethoxy-benzenesulfonamide(202 mg, 35%) as a pale yellow solid.

ESI MS m/e 582, M+H⁺; ¹H NMR (300 MHz, CDCl₃) δ 7.88 (d, J=8.4 Hz, 1 H),7.73 (d, J=8.4 Hz, 1 H), 7.64 (d, J=8.9 Hz, 2 H), 7.51-7.58 (m, 3 H),7.44 (dd, J=8.4, 1.7 Hz, 1 H), 7.07-7.24 (m, 1 H), 7.02 (d, J=8.9 Hz, 2H), 3.32 (s, 6 H).

Example 33

4-Bromo-N-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-phenyl}-2-trifluoromethoxy-benzenesulfonamide

Step A: Synthesis of[4-(tert-butoxycarbonylamino-methyl)-phenyl]-carbamic acid benzyl ester.

To a solution of 4-aminomethyl-phenylamine (3.00 g, 24.6 mmol) in CHCl₃(30 mL) was added triethylamine (2.61 g, 25.8 mmol). After cooling on anice-bath, (Boc)₂O (5.63 g, 25.8 mmol) was added dropwise. The reactionmixture was stirred at ambient temperature for 55 min and poured intosaturated aqueous NaHCO₃. The aqueous layer was extracted with CHCl₃(three times) and the combined organic layer was dried over MgSO₄,filtered, and concentrated to give a pale yellow oil. To a solution ofthe above oil in CHCl₃ (30 mL) was added diisopropylethylamine (3.33 g,25.8 mmol). The resulting solution was cooled to 4° C. and ZCl (4.40 g,25.8 mmol) was added below 10° C. over 5 min. The reaction mixture wasstirred at ambient temperature for 12 hr, and poured into saturatedaqueous NaHCO₃. The aqueous layer was extracted with CHCl₃ (threetimes). The combined organic layer was dried over MgSO₄, filtered,concentrated, and purified by flash chromatography (silica gel, 2% MeOHin CHCl₃) to give [4-(tert-butoxycarbonylamino-methyl)-phenyl]-carbamicacid benzyl ester (2.64 g, 30%) as a white solid.

ESI MS m/e 379, M+Na⁺; ¹H NMR (300 MHz, CDCl₃) δ 7.11-7.44 (m, 9 H),6.76 (brs, 1 H), 5.19 (s, 2 H), 4.81 (brs, 1 H), 4.25 (d, J=5.1 Hz, 2H), 1.45 (s, 9 H).

Step B: Synthesis of (4-aminomethyl-phenyl)-carbamic acid benzyl esterhydrochloride.

A solution of [4-(tert-butoxycarbonylamino-methyl)-phenyl]-carbamic acidbenzyl ester (1.25 g, 3.51 mmol) in EtOAc (20 mL) was cooled on anice-bath and 4 M hydrogen chloride in EtOAc (20 mL) was added. Themixture was stirred at ambient temperature for 20 min. The precipitatewas collected by filtration, washed with EtOAc, and dried under reducedpressure to give (4-aminomethyl-phenyl)-carbamic acid benzyl esterhydrochloride (957 mg, 93%) as a white solid.

ESI MS m/e 279, M+Na⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 9.90 (s, 1 H), 8.37(brs, 3H), 7.29-7.55 (m, 9 H), 5.15 (s, 2 H), 3.85-4.01 (m, 2 H).

Step C: Synthesis of{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-phenyl}-carbamic acidbenzyl ester.

Using the procedure for the step C of example 3, the title compound wasobtained.

ESI MS m/e 428, M+H⁺; ¹H NMR (300 MHz, CDCl₃) δ 7.82 (d, J=7.5 Hz, 1 H),7.25-7.52 (m, 11 H), 6.98-7.07 (m, 1 H), 6.74 (brs, 1 H), 5.28 (brs, 1H), 5.19 (s, 2 H), 4.65 (d, J=5.9 Hz, 2 H), 3.25(s, 6 H).

Step D: Synthesis of4-bromo-N-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-phenyl}-2-trifluoromethoxy-benzenesulfonamide.

To a solution of{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-phenyl}-carbamic acidbenzyl ester (318 mg, 0.744 mmol) in MeOH (3 mL) was added 5% Pd/C (30mg). The mixture was stirred at 50° C. under hydrogen atmosphere for41.5 hr, filtered through a pad of celite, and concentrated. To asolution of 4-bromo-2-trifluoromethoxy-benzenesulfonyl chloride (505 mg,1.49 mmol) in CH₂Cl₂ (12 mL) was added PVP (6 mL). To the resultingsuspension was added a solution of the above residue in CH₂Cl₂ (10 mL).The mixture was stirred at ambient temperature for 1.5 days, filtered,poured into saturated aqueous NaHCO₃. The aqueous layer was extractedwith CHCl₃ (three times). The combined organic layer was dried overMgSO₄, filtered, concentrated, and purified by medium-pressure liquidchromatography (NH-silica gel, 33% EtOAc in hexane) to give4-bromo-N-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-phenyl}-2-trifluoromethoxy-benzenesulfonamide(330 mg, 74%) as a pale brown solid.

ESI MS m/e 596, M+H⁺; ¹H NMR (300 MHz, CDCl₃) δ 7.83 (d, J=8.4 Hz, 1 H),7.77 (d, J=8.4 Hz, 1 H), 7.41-7.60 (m, 4 H), 7.22 (d, J=8.6 Hz, 2 H),7.08-7.18 (m, 1 H), 6.99 (d, J=8.6 Hz, 2 H), 4.56 (d, J=5.6 Hz, 2 H),3.34 (s, 6 H).

Example 34

trans-N⁴,N⁴-Dimethyl-N²-{4-[(2-trifluoromethoxy-benzylamino)-methyl]-cyclohexylmethyl}-quinazoline-2,4-diamine

Step A: Synthesis oftrans-N⁴,N⁴-dimethyl-N²-{4-[(2-trifluoromethoxy-benzylamino)-methyl]-cyclohexylmethyl}-quinazoline-2,4-diamine.

Using the procedure for the step B of example 15, the title compound wasobtained.

ESI MS m/e 510, M+Na⁺; ¹H NMR (300 MHz, CDCl₃) δ 7.80 (d, J=8.2 Hz, 1H), 7.39-7.57 (m, 3 H), 7.15-7.35 (m, 3 H), 7.02 (ddd, J=8.3, 6.0, 2.2Hz, 1 H), 3.83 (s, 2 H), 3.35 (t, J=6.3 Hz, 2 H), 3.27 (s, 6 H), 2.45(d, J=6.5 Hz, 2 H), 1.69-2.04 (m, 4 H), 1.37-1.69 (m, 2 H), 0.84-1.12(m, 4 H).

Example 35

N⁴,N⁴-Dimethyl-N²-[1-(2-trifluoromethoxy-benzyl)-piperidin-4-yl]-quinazoline-2,4-diamine

Step A: Synthesis ofN⁴,N⁴-dimethyl-N²-[1-(2-trifluoromethoxy-benzyl)-piperidin-4-yl]-quinazoline-2,4-diamine.

Using the procedure for the step B of example 15, the title compound wasobtained.

ESI MS m/e 468, M+Na⁺; ¹H NMR (300 MHz, CDCl₃) δ 7.80 (d, J=7.8 Hz, 1H), 7.37-7.63 (m, 3 H), 7.17-7.35 (m, 3 H), 7.02 (ddd, J=8.3, 6.4, 1.9Hz, 1 H), 5.12 (brs, 1 H), 3.86-4.07 (m, 1 H), 3.60 (s, 2 H), 3.26 (s, 6H), 2.74-2.94 (m, 2 H), 2.18-2.37 (m, 2 H), 1.98-2.15 (m, 2 H),1.45-1.69 (m, 2 H).

Example 36

trans-N⁴,N⁴-Dimethyl-N²-(4-{[(3-trifluoromethoxy-biphenyl-4-ylmethyl)-amino]-methyl}-cyclohexylmethyl)-quinazoline-2,4-diaminedihydrochloride

Step A: Synthesis oftrans-N⁴,N⁴-dimethyl-N²-(4-{[(3-trifluoromethoxy-biphenyl-4-ylmethyl)-amino]-methyl}-cyclohexylmethyl)-quinazoline-2,4-diamine-dihydrochloride

To a solution oftrans-N²-{4-[(4-bromo-2-trifluoromethoxy-benzylamino)-methyl]-cyclohexylmethyl}-N⁴,N⁴-dimethyl-quinazoline-2,4-diamineobtained in step B of example 15 (300 mg, 0.529 mol) in toluene (6.6 mL)were added MeOH (2.2 mL), 2 M aqueous K₂CO₃ (2.2 mL), phenylboronic acid(77 mg, 0.635 mmol), and tetrakis (triphenylphosphine) palladium (61 mg,0.053 mmol). The reaction mixture was stirred at 130° C. for 12 hr. Themixture was poured into water, and the aqueous layer was extracted withCHCl₃ (three times). The combined organic layer was dried over MgSO₄,filtered, concentrated and, purified by flash chromatography (NH-silicagel, 33% CHCl₃ in hexane and silica gel, 9% MeOH in CHCl₃) to give paleyellow oil. To a solution of above oil in EtOAc (2 mL) was added 4 Mhydrogen chloride in EtOAc (0.1 mL). The mixture was stirred at ambienttemperature for 20 min and concentrated. A solution of the residue inEt₂O (2 mL) was stirred at ambient temperature for 30 min. Theprecipitate was collected by filtration, washed with Et₂O, and driedunder reduced pressure to givetrans-N⁴,N⁴-dimethyl-N²-(4-{[(3-trifluoromethoxy-biphenyl-4-ylmethyl)-amino]-methyl}-cyclohexylmethyl)-quinazoline-2,4-diaminedihydrochloride (70 mg, 21%) as a white solid.

ESI MS m/e 564, M (free)+H⁺; ¹H NMR (300 MHz, CDCl₃) δ 13.27 (s, 1 H),9.96 (brs, 2 H), 8.17-8.32 (m, 2 H), 7.89 (d, J=7.9 Hz, 1 H), 7.34-7.64(m, 9 H), 7.20 (t, J=7.7 Hz, 1 H), 4.29 (brs, 2 H), 3.50 (s, 6 H), 3.28(t, J=6.1 Hz, 2 H), 2.69 (brs, 2 H), 1.79-2.11 (m, 4 H), 1.44-1.68 (m, 2H), 0.91-1.16 (m, 4 H).

Example 37

cis-N²-{4-[2-(4-Bromo-2-trifluoromethoxy-phenyl)-ethylamino]-cyclohexyl}-N⁴,N⁴-dimethyl-quinazoline-2,4-diaminedihydrochloride

Step A: Synthesis of (4-bromo-2-trifluoromethoxy-phenyl)-acetaldehyde.

To a suspension of (methoxymethyl) triphenylphosphonium chloride (5.29g, 14.9 mol) in Et₂O (50 mL) was added 1.8 M phenyl lithium in 30% Et₂Oin cyclohexane (8.58 mL, 15.5 mmol). The mixture was stirred at ambienttemperature for 10 min. To the reaction mixture was added4-bromo-2-trifluoromethoxy-benzaldehyde (4 g, 14.9 mmol) in Et₂O (18mL). The mixture was stirred at ambient temperature for 4 hr, filtrated,and concentrated. To the above residue was added 10% H₂SO₄ in AcOH (40mL). The mixture was stirred at ambient temperature for 90 min. Thesolution was poured into H₂O, and the aqueous layer was extracted withCHCl₃ (three times). The combined organic layer was washed withsaturated aqueous NaHCO₃, washed with brine, dried over MgSO₄, filtered,concentrated, and purified by flash chromatography (silica gel, 9% EtOAcin hexane) to give (4-bromo-2-trifluoromethoxy-phenyl)-acetaldehyde(1.25 g, 30%) as a pale brown oil.

ESI MS m/e 284, M+H⁺; ¹H NMR (200 MHz, CDCl₃) δ 9.74 (t, J=1.5 Hz, 1 H),7.41-7.51 (m, 2 H), 7.16 (d, J=8.4 Hz, 1 H), 3.75 (d, J=1.5 Hz, 2 H).

Step B: Synthesis ofcis-N²{4-[2-(4-bromo-2-trifluoromethoxy-phenyl)-ethylamino]-cyclohexyl}-N⁴,N⁴-dimethyl-quinazoline-2,4-diaminedihydrochloride.

To a suspension ofcis-N²-(4-amino-cyclohexyl)-N⁴,N⁴-dimethyl-quinazoline-2,4-diamineobtained in step C of example 9 (300 mg, 1.05 mmol) in CH₂Cl₂ (3 mL)were added (4-bromo-2-trifluoromethoxy-phenyl)-acetaldehyde (357 mg,1.26 mmol), AcOH (76 mg, 1.26 mmol), and NaBH(OAc)₃ (334 mg, 1.57 mmol).The reaction mixture was stirred at ambient temperature for 4.5 hr. Thereaction was quenched with saturated aqueous NaHCO₃ The aqueous layerwas extracted with CHCl₃ (three times). The combined organic layer wasdried over MgSO₄, filtered, concentrated, and purified by flashchromatography (NH-silica gel, 50% EtOAc in hexane) to give a paleyellow solid. To a solution of above solid in EtOAc (0.8 mL) was added 4M hydrogen chloride in EtOAc (0.25 mL). The mixture was stirred atambient temperature for 30 min and concentrated. A solution of theresidue in Et₂O (2 mL) was stirred at ambient tempareture for 30 min.The precipitate was collected by filtration, washed with Et₂O, and driedunder reduced pressure to givecis-N²-{4-[2-(4-bromo-2-trifluoromethoxy-phenyl)-ethylamino]-cyclohexyl}-N⁴,N⁴-dimethyl-quinazoline-2,4-diaminedihydrochloride (161 mg, 25%) as a white solid.

ESI MS m/e 552, M (free)⁺; ¹H NMR (200 MHz, CDCl₃) δ 12.66 (brs, 1 H),9.91 (brs, 2 H), 8.71 (brs, 1 H), 7.93 (d, J=6.6 Hz, 1 H), 7.19-7.77 (m,6 H), 4.31 (brs, 1 H), 3.54 (s, 6 H), 3.09-3.78 (m, 5 H), 2.00-2.48 (m,6 H), 1.62-1.96 (m, 2 H).

Example 38

cis-N⁴,N⁴-Dimethyl-N²-[4-(2-trifluoromethoxy-benzylamino)-cyclohexyl]-quinazoline-2,4-diaminedihydrochloride

Step A: Synthesis ofcis-N⁴,N⁴-dimethyl-N²-[4-(2-trifluoromethoxy-benzylamino)-cyclohexyl]-quinazoline-2,4-diaminedihydrochloride.

Using the procedure for the step B of example 37, the title compound wasobtained.

ESI MS m/e 460, M (free)+H⁺; ¹H NMR (300 MHz, CDCl₃) δ 8.68 (d, J=7.6Hz, 1 H), 8.19-8.33 (m, 1 H), 7.95 (d, J=8.2 Hz, 1 H), 7.66 (t, J=7.7Hz, 1 H), 7.47 (d, J=8.1 Hz, 1 H), 7.18-7.44 (m, 4 H), 4.35 (s, 2 H),4.15-4.47 (m, 1 H), 3.53 (s, 6 H), 3.02-3.31 (m, 1 H), 1.95-2.37 (m, 6H), 1.51-1.85 (m, 2 H).

Example 39

cis-N²-[4-(4-Bromo-2-trifluoromethoxy-benzylamino)-cyclohexyl]-N⁴,N⁴-dimethyl-quinazoline-2,4-diaminedihydrochloride

Step A: Synthesis ofcis-N²-[4-(4-bromo-2-trifluoromethoxy-benzylamino)-cyclohexyl]-N⁴,N⁴-dimethyl-quinazoline-2,4-diaminedihydrochloride.

Using the procedure for the step A of example 2, the title compound wasobtained.

ESI MS m/e 538, M (free)+H⁺; ¹H NMR (300 MHz, CDCl₃) δ 8.77 (d, J=7.5Hz, 1 H), 8.11 (d, J=8.4 Hz, 1 H), 7.92 (d, J=8.6 Hz, 1 H), 7.67 (t,J=7.7 Hz, 1 H), 7.41-7.53 (m, 2 H), 7.37 (s, 1 H), 7.28 (t, J=7.8 Hz, 1H), 4.19-4.40 (m, 1 H), 4.26 (s, 2 H), 3.52 (s, 7 H), 3.07-3.25 (m, 1H), 2.00-2.39 (m, 6 H), 1.61-1.88 (m, 2 H).

Example 40

cis-N-[4-(4-Dimethylamino-quinazolin-2-ylamino)-cyclohexylmethyl]-2-trifluoromethoxy-benzenesulfonamidehydrochloride

Step A: Synthesis ofcis-N-[4-(4-dimethylamino-quinazolin-2-ylamino)-cyclohexylmethyl]-2-trifluoromethoxy-benzenesulfonamidehydrochloride.

To a solution ofcis-[4-(4-dimethylamino-quinazolin-2-ylamino)-cyclohexylmethyl]-carbamicacid benzyl ester obtained in step B of example 24 (4.57 g, 10.5 mmol)in MeOH (46 mL) was added 5% Pd/C (460 mg). The mixture was stirred at50° C. under hydrogen atmosphere for 3 days, filtered, and concentratedto give a white solid (3.79 g). To a solution of the above solid (500mg, 1.67 mmol) in CH₂Cl₂ (5 mL) was added diisopropylethylamine (440 μL,2.53 mmol). The mixture was cooled on an ice-bath and a solution of2-trifluoromethoxy-benzenesulfonyl chloride (457 mg, 1.75 mmol) inCH₂Cl₂ (2 mL) was added dropwise. The reaction mixture was stirred on anice-bath for 10 hr. The reaction was quenched with saturated aqueousNaHCO₃ The aqueous layer was extracted with CHCl₃ (three times). Thecombined organic layer was dried over MgSO₄, filtered, concentrated,purified by medium-pressure liquid chromatography (NH-silica gel, 33%EtOAc in hexane), and concentrated. To a solution of the residue inEtOAc (1 mL) was added 4 M hydrogen chloride in EtOAc (5 mL). Thereaction mixture was stirred at ambient temperature for 30 min, andconcentrated. A solution of the residue in Et₂O (10 mL) was stirred atambient temperature for 1 hr and the precipitate was collected byfiltration to givecis-N-[4-(4-dimethylamino-quinazolin-2-ylamino)-cyclohexylmethyl]-2-trifluoromethoxy-benzenesulfonamidehydrochloride (262 mg, 34%) as a white solid.

ESI MS m/e 524, M (free)+W; ¹H NMR (300 MHz, CDCl₃) δ 13.18 (s, 1 H),8.75 (d, J=7.6 Hz, 1 H), 8.03 (dd, J=8.0, 1.7 Hz, 1 H), 7.89 (d, J=8.2Hz, 1 H), 7.56-7.71 (m, 2 H), 7.34-7.55 (m, 3 H), 7.24 (t, J=7.5 Hz, 1H), 4.99 (t, J=6.5 Hz, 1 H), 4.20-4.33 (m, 1 H), 3.50 (s, 6 H), 2.88 (t,J=6.3 Hz, 2 H), 1.78-1.99 (m, 2 H), 1.38-1.77 (m, 7 H).

Example 41

cis-N²-{4-[(4-Bromo-2-trifluoromethoxy-benzylamino)-methyl]-cyclohexyl}-N⁴,N⁴-dimethyl-quinazoline-2,4-diaminedihydrochloride

Step A: Synthesis ofcis-N²-{4-[(4-bromo-2-trifluoromethoxy-benzylamino)-methyl]-cyclohexyl}-N⁴,N⁴-dimethyl-quinazoline-2,4-diaminedihydrochloride.

To a solution ofcis-[4-(4-dimethylamino-quinazolin-2-ylamino)-cyclohexylmethyl]-carbamicacid benzyl ester obtained in step B of example 24 (4.57 g, 10.5 mmol)in MeOH (46 mL) was added 5% Pd/C (460 mg). The mixture was stirred at50° C. under hydrogen atmosphere for 3 days, filtered, and concentratedto give a colorless solid (3.79 g). To a solution of the above solid(500 mg, 1.67 mmol) in CH₂Cl₂ (5 mL) were added4-bromo-2-trifluoromethoxy-benzaldehyde obtained in step A of example 13(449 mg, 1.67 mmol), AcOH (100 mg, 1.67 mmol), and NaBH(OAc)₃ (531 g,2.51 mmol). The reaction mixture was stirred at ambient temperature withCaCl₂ tube for 9 hr, poured into saturated aqueous NaHCO₃, and theaqueous layer was extracted with CHCl₃ (three times). The combinedorganic layer was dried over MgSO₄, filtered, concentrated, purified bymedium-pressure liquid chromatography (NH-silica gel, 25% EtOAc inhexane), and concentrated. To a solution of the residue in EtOAc (1 mL)was added 4 M hydrogen chloride in EtOAc (5 mL). The reaction mixturewas stirred at ambient temperature for 30 min, and concentrated. Asolution of the residue in Et₂O (10 mL) was stirred at ambienttemperature for 1 hr and the precipitate was collected by filtration togivecis-N²-{4-[(4-bromo-2-trifluoromethoxy-benzylamino)-methyl]-cyclohexyl}-N⁴,N⁴-dimethyl-quinazoline-2,4-diaminedihydrochloride (147 mg, 34%) as a white solid.

ESI MS m/e 552, M (free)+W; ¹H NMR (300 MHz, CDCl₃) δ 12.62 (s, 1 H),10.07 (brs, 2 H), 8.66 (d, J=7.6 Hz, 1 H), 8.22 (d, J=8.4 Hz, 1 H), 7.90(d, J=8.4 Hz, 1 H), 7.65 (t, J=7.6 Hz, 1 H), 7.52 (dd, J=8.3, 1.8 Hz, 1H), 7.33-7.48 (m, 2 H), 7.26 (t, J=7.5 Hz, 1 H), 4.11-4.36 (m, 3 H),3.51 (s, 6 H), 2.76-2.97 (m, 2 H), 1.51-2.27 (m, 9 H).

Example 42

cis-N⁴,N⁴-Dimethyl-N²-{4-[(2-trifluoromethoxy-benzylamino)-methyl]-cyclohexyl}-quinazoline-2,4-diaminedihydrochloride

Step A: Synthesis ofcis-N⁴,N⁴-dimethyl-N²-{4-[(2-trifluoromethoxy-benzylamino)-methyl]-cyclohexyl}-quinazoline-2,4-diaminedihydrochloride.

Using the procedure for the step A of example 41, the title compound wasobtained.

ESI MS m/e 474, M (free)+H⁺; ¹H NMR (300 MHz, CDCl₃) δ 12.81 (s, 1 H),9.97 (brs, 1 H), 8.69 (d, J=7.5 Hz, 1 H), 8.16-8.28 (m, 1 H), 7.90 (d,J=8.4 Hz, 1 H), 7.63 (t, J=7.6 Hz, 1 H), 7.18-7.51 (m, 4 H), 4.31 (brs,2 H), 4.15-4.30 (m, 1 H), 3.50 (s, 6 H), 2.70-2.94 (m, 2 H), 1.41-2.28(m, 10 H).

Example 43

cis-3-Trifluoromethoxy-biphenyl-4-sulfonic acid[4-(4-dimethylamino-quinazolin-2-ylamino)-cyclohexyl]-amidehydrochloride

Step A: Synthesis of cis-3-trifluoromethoxy-biphenyl-4-sulfonic acid[4-(4-dimethylamino-quinazolin-2-ylamino)-cyclohexyl]-amidehydrochloride.

Using the procedure for the step A of example 36, the title compound wasobtained.

ESI MS m/e 586, M (free)+H⁺; ¹H NMR (300 MHz, CDCl₃) δ 13.20 (brs, 1 H),8.82 (d, J=8.1 Hz, 1 H), 8.09 (d, J=8.6 Hz, 1 H), 7.88 (d, J=7.8 Hz, 1H), 7.40-7.73 (m, 8 H), 7.25 (t, J=8.4 Hz, 1 H), 5.41 (d, J=8.6 Hz, 1H), 4.07-4.22 (m, 1 H), 3.49 (s, 6 H), 3.37-3.62 (m, 1 H), 1.57-2.01 (m,8 H).

Example 44

cis-N²-{4-[Bis-(4-bromo-2-trifluoromethoxy-benzyl)-amino]-cyclohexyl}-N⁴,N⁴-dimethyl-quinazoline-2,4-diaminedihydrochloride

Step A: Synthesis ofcis-N²-{4-[bis-(4-bromo-2-trifluoromethoxy-benzyl)-amino]-cyclohexyl}-N⁴,N⁴-dimethyl-quinazoline-2,4-diaminedihydrochloride.

Using the procedure for the step B of example 37, the title compound wasobtained.

ESI MS m/e 790, M (free)+H⁺; ¹H NMR (300 MHz, CDCl₃) δ 12.50-12.82 (m, 2H), 9.50-9.69 (m, 1 H), 8.39 (d, J=8.1 Hz, 2 H), 7.91 (d, J=8.1 Hz, 1H), 7.66 (t, J=7.8 Hz, 1 H), 7.48 (t, J=8.7 Hz, 2 H), 7.07-7.43 (m, 4H), 4.06-4.67 (m, 5 H), 3.51 (s, 6 H), 2.97-3.27 (m, 1 H), 2.21-2.59 (m,4 H), 1.89-2.17 (m, 2 H), 1.36-1.82 (m, 2 H)

Example 45

cis-N⁴,N⁴-Dimethyl-N²-{4-[(3-trifluoromethoxy-biphenyl-4-ylmethyl)-amino]-cyclohexyl}-quinazoline-2,4-diaminedihydrochloride

Step A: Synthesis ofcis-N⁴,N⁴-dimethyl-N²-{4-[(3-trifluoromethoxy-biphenyl-4-ylmethyl)-amino]-cyclohexyl}-quinazoline-2,4-diaminedihydrochloride.

Using the procedure for the step A of example 43, the title compound wasobtained.

ESI MS m/e 536, M (free)+H⁺; ¹H NMR (300 MHz, CDCl₃) δ 12.63 (brs, 1 H),10.07 (brs, 2 H), 8.68 (d, J=7.3 Hz, 1 H), 8.33 (d, J=8.1 Hz, 1 H), 7.90(d, J=8.4 Hz, 1 H), 7.17-7.68 (m, 10 H), 4.40 (s, 2 H), 4.19-4.33 (m, 1H), 3.50 (s, 6 H), 3.16-3.37 (m, 1 H), 2.03-2.48 (m, 6 H), 1.64-1.88 (m,2 H).

Example 46

trans-N²-[4-(4-Bromo-2-trifluoromethoxy-benzylamino)-cyclohexyl]-N⁴,N⁴-dimethyl-quinazoline-2,4-diaminedihydrochloride

Step A: Synthesis oftrans-N²-[4-(4-bromo-2-trifluoromethoxy-benzylamino)-cyclohexyl]-N⁴,N⁴-dimethyl-quinazoline-2,4-diaminedihydrochloride.

Using the procedure for the step B of example 37, the title compound wasobtained.

ESI MS m/e 537, M (free)⁺; ¹H NMR (300 MHz, CDCl₃) δ 13.00 (brs, 1 H),10.08 (brs, 2 H), 8.40 (d, J=7.2 Hz, 1 H), 8.05 (d, J=8.2 Hz, 1 H), 7.91(d, J=8.4 Hz, 1 H), 7.65 (t, J=7.7 Hz, 1 H), 7.38-7.57 (m, 3 H), 7.26(t, J=7.6 Hz, 1 H), 4.17 (s, 2 H), 3.83-4.06 (m, 1 H), 3.53 (s, 6 H),2.76-2.99 (m, 1 H), 2.09-2.46 (m, 4 H), 1.74-2.00 (m, 2 H), 1.28-1.58(m, 2 H).

Example 47

1-(4-Bromo-2-trifluoromethoxy-phenyl)-1-[4-(4-dimethylamino-quinazolin-2-ylamino)-piperidin-1-yl]-methanonehydrochloride

Step A: Synthesis of(4-bromo-2-trifluoromethoxy-phenyl)-[4-(4-dimethylamino-quinazolin-2-ylamino)-piperidin-1-yl]-methanonehydrochloride.

To a solution of 4-bromo-2-trifluoromethoxy-benzoic acid obtained instep B of example 13 (440 mg, 1.47 mmol) in CH₂Cl₂ (5 mL) were added DMF(1.1 μL, 15 μmol) and SOCl₂ (175 μL, 2.09 mmol). The mixture was stirredat reflux for 30 min and concentrated to give acid chloride as a paleyellow oil. To a solution ofN⁴,N⁴-dimethyl-N²-piperidin-4-yl-quinazoline-2,4-diamine obtained instep B of example 30 (400 mg, 1.47 mmol) in CH₂Cl₂ (4 mL) was addeddiisopropylethylamine (538 μL, 3.08 mmol). The mixture was cooled at 4°C. and a solution of above acid chloride in CH₂Cl₂ (3 mL) was addedbelow 5° C. The reaction mixture was stirred at 4° C. for 3 hr. Thereaction was quenched with saturated aqueous NaHCO₃, and the aqueouslayer was extracted with CHCl₃ (three times). The combined organic layerwas dried over MgSO₄, filtered, concentrated, and purified by flashchromatography (NH-silica gel, 25% EtOAc in hexane) to give a paleyellow oil. To a solution of above oil in EtOAc (1 mL) was added 4 Mhydrogen chloride in EtOAc (0.26 mL). The mixture was stirred at ambienttemperature for 50 min and concentrated. A solution of the residue inEt₂O (5 mL) was stirred at ambient tempareture for 30 min. Theprecipitate was collected by filtration, washed with Et₂O, and driedunder reduced pressure to give(4-bromo-2-trifluoromethoxy-phenyl)-[4-(4-dimethylamino-quinazolin-2-ylamino)-piperidin-1-yl]-methanonehydrochloride (126 mg, 16%) as a white solid.

ESI MS m/e 538, M (free)+H⁺; ¹H NMR (200 MHz, CDCl₃) δ 13.35 (brs, 1 H),9.06 (d, J=7.5 Hz, 1 H), 7.93 (d, J=8.4 Hz, 1 H), 7.67 (dt, J=7.7, 0.9Hz, 1 H), 7.43-7.61 (m, 3 H), 7.18-7.41 (m, 2 H), 4.00-4.44 (m, 2 H),3.54 (s, 6 H), 3.03-3.78 (m, 3 H), 1.52-2.24 (m, 4 H).

Example 48

cis-4-Bromo-N-[4-(4-dimethylamino-quinazolin-2-ylamino)-cyclohexyl]-2-trifluoromethoxy-benzamidedihydrochloride

Step A: Synthesis of4-bromo-N-[4-(4-dimethylamino-quinazolin-2-ylamino)-cyclohexyl]-2-trifluoromethoxy-benzamidedihydrochloride.

Using the procedure for the step A of example 47, the title compound wasobtained.

ESI MS m/e 551, M (free)⁺; ¹H NMR (200 MHz, CDCl₃) δ 13.24 (brs, 1 H),8.95 (d, J=7.9 Hz, 1 H), 7.92 (d, J=8.4 Hz, 1 H), 7.71 (d, J=8.4 Hz, 1H), 7.60-7.67 (m, 1 H), 7.44-7.58 (m, 3 H), 7.20-7.34 (m, 1 H), 6.57 (d,J=8.4 Hz, 1 H), 4.00-4.41 (m, 2 H), 3.53 (s, 6 H), 1.66-2.04 (m, 8 H).

Example 49

cis-4-Bromo-N-[4-(4-dimethylamino-quinazolin-2-ylamino)-cyclohexylmethyl]-2-trifluoromethoxy-benzamidehydrochloride

Step A: Synthesis of4-bromo-N-[4-(4-dimethylamino-quinazolin-2-ylamino)-cyclohexylmethyl]-2-trifluoromethoxy-benzamidehydrochloride.

Using the procedure for the step A of example 47, the title compound wasobtained.

ESI MS m/e 565, M (free)⁺; ¹H NMR (200 MHz, CDCl₃) δ 13.20 (brs, 1 H),8.93 (d, J=7.9 Hz, 1 H), 7.90 (d, J=8.4 Hz, 1 H), 7.84 (d, J=8.4 Hz, 1H), 7.42-7.70 (m, 4 H), 7.18-7.34 (m, 1 H), 6.87 (t, J=5.5 Hz, 1 H),4.34 (brs, 1 H), 3.51 (s, 6 H), 3.43 (t, J=5.7 Hz, 2 H), 1.52-2.17 (m, 9H).

Example 50

cis-N²-[4-(4-Bromo-2-trifluoromethoxy-benzylamino)-cyclohexyl]-IV-methyl-quinazoline-2,4-diaminedihydrochloride

Step A: Synthesis of (2-chloro-quinazolin-4-yl)-methyl-amine.

A solution of 2,4-dichloro-quinazoline obtained in step A of example 1(125 g, 628 mmol) in THF (1 L) was cooled to 4° C. and 40% aqueous MeNH₂(136 mL, 1.57 mol) was added. The mixture was stirred at ambienttemperature for 80 min. The solution was alkalized with saturatedaqueous NaHCO₃ (pH=9) and concentrated. The precipitate was collected byfiltration, washed with H₂O and hexane, and dried at 80° C. to give(2-chloro-quinazolin-4-yl)-methyl-amine (114 g, 94%) as a white solid.

ESI MS m/e 193, M⁺; ¹H NMR (300 MHz, CDCl₃) δ 7.68-7.78 (m, 3 H),7.39-7.48 (m, 1 H), 6.34 (brs, 1 H), 3.22 (d, J=4.8 Hz, 3 H).

Step B: Synthesis ofcis-[4-(4-methylamino-quinazolin-2-ylamino)-cyclohexyl]-carbamic acidtert-butyl ester.

Using the procedure for the step G of example 1, the title compound wasobtained.

ESI MS m/e 372, M+H⁺; ¹H NMR (300 MHz, CDCl₃) δ 7.36-7.56 (m, 3 H), 7.06(ddd, J=8.2, 6.8, 1.3 Hz, 1 H), 5.71 (brs, 1 H), 5.10 (brs, 1 H),4.45-4.72 (m, 1 H), 4.00-4.26 (m, 1 H), 3.49-3.76 (m, 1 H), 3.12 (d,J=4.8 Hz, 3 H), 1.50-1.93 (m, 8 H), 1.46 (s, 9 H).

Step C: Synthesis ofcis-N²-[4-(4-bromo-2-trifluoromethoxy-benzylamino)-cyclohexyl]-N⁴-methyl-quinazoline-2,4-diaminedihydrochloride.

To a suspension ofcis-[4-(4-methylamino-quinazolin-2-ylamino)-cyclohexyl]-carbamic acidtert-butyl ester (1.75 g, 4.71 mmol) in EtOAc (5 mL) and CHCl₃ (10 mL)was added 4 M hydrogen chloride in EtOAc (15 mL). The reaction mixturewas stirred at ambient temperature for 2 hr, and concentrated. Theresidue was alkalized with saturated aqueous NaHCO₃ and the aqueouslayer was extracted with CHCl₃ (three times). The combined organic layerwas dried over MgSO₄, filtered, concentrated (2.15 g). To a suspensionof the above residue (300 mg, 1.11 mmol) in CH₂Cl₂ (3 mL) were added4-bromo-2-trifluoromethoxy-benzaldehyde obtained in Step A of Example 13(297 mg, 1.10 mmol), AcOH (66 mg, 1.10 mmol), and NaBH(OAc)₃ (351 mg,1.66 mmol). The reaction mixture was stirred at ambient temperature withCaCl₂ tube for 4 hr, poured into saturated aqueous NaHCO₃, and theaqueous layer was extracted with CHCl₃ (three times). The combinedorganic layer was dried over MgSO₄, filtered, concentrated, purified bymedium-pressure liquid chromatography (NH-silica gel, 50% EtOAc inhexane), and concentrated to give a pale yellow oil (91 mg). To asolution of the residue (71 mg) in EtOAc (1 mL) was added 4 M hydrogenchloride in EtOAc (5 mL). The reaction mixture was stirred at ambienttemperature for 30 min, and concentrated. A solution of the residue inEt₂O (10 mL) was stirred at ambient temperature for 1 hr and theprecipitate was collected by filtration to givecis-N²-[4-(4-bromo-2-trifluoromethoxy-benzylamino)-cyclohexyl]-N-4-methyl-quinazoline-2,4-diaminedihydrochloride (62 mg, 20%) as a white solid.

ESI MS m/e 524, M (free)+H⁺; ¹H NMR (300 MHz, CDCl₃) δ 7.34-7.57 (m, 6H), 7.05 (ddd, J=8.2, 6.8, 1.4 Hz, 1 H), 5.52 (brs, 1 H), 4.09-4.27 (m,1 H), 3.82 (s, 2 H), 3.12 (d, J=4.8 Hz, 3 H), 2.57-2.72 (m, 1 H),1.41-1.94 (m, 8 H).

Example 51

cis-N²-{4-[2-(4-Bromo-2-trifluoromethoxy-phenyl)-ethylamino]-cyclohexyl}-N⁴-methyl-quinazoline-2,4-diaminedihydrochloride

Step A: Synthesis ofcis-N²-{4-[2-(4-bromo-2-trifluoromethoxy-phenyl)-ethylamino]-cyclohexyl}-N⁴-methyl-quinazoline-2,4-diaminedihydrochloride.

Using the procedure for the step C of example 50, the title compound wasobtained.

ESI MS m/e 538, M (free)+H⁺; ¹H NMR (300 MHz, CDCl₃) δ 12.18 (brs, 1 H),9.93 (brs, 3 H), 8.74 (d, J=6.2 Hz, 1 H), 7.71-7.94 (m, 1 H), 7.60 (t,1H, J=7.7 Hz, 1 H), 7.21-7.45 (m, 5 H), 3.94-4.26 (m, 1 H), 3.35-3.58(m, 2 H), 3.08-3.33 (m, 3 H), 2.94 (brs, 3 H), 1.64-2.42 (m, 8 H).

Example 52

cis-N⁴-Methyl-N²-[4-(2-trifluoromethoxy-benzylamino)-cyclohexyl]-quinazoline-2,4-diaminedihydrochloride

Step A: Synthesis ofcis-N⁴-methyl-N²-[4-(2-trifluoromethoxy-benzylamino)-cyclohexyl]-quinazoline-2,4-diaminedihydrochloride.

Using the procedure for the step C of example 50, the title compound wasobtained.

ESI MS m/e 446, M (free)+H⁺; ¹H NMR (300 MHz, CDCl₃) δ 7.36-7.56 (m, 4H), 7.17-7.33 (m, 3 H), 7.04 (ddd, 1H, J=8.2, 6.8, 1.4 Hz, 1 H), 5.66(brs, 1 H), 5.18 (brs, 1 H), 4.11-4.27 (m, 1 H), 3.87 (s, 2 H), 3.10 (d,J=4.8 Hz, 3 H), 2.60-2.74 (m, 1 H), 1.45-1.95 (m, 8 H).

Example 53

cis-4-Bromo-N-[4-(4-methylamino-quinazolin-2-ylamino)-cyclohexyl]-2-trifluoromethoxy-benzamidehydrochloride

Step A: Synthesis ofcis-4-bromo-N-[4-(4-methylamino-quinazolin-2-ylamino)-cyclohexyl]-2-trifluoromethoxy-benzamidehydrochloride.

To a suspension ofcis-[4-(4-methylamino-quinazolin-2-ylamino)-cyclohexyl]-carbamic acidtert-butyl ester obtained in step B of example 50 (1.75 g, 4.71 mmol) inEtOAc (5 mL) and CHCl₃ (10 mL) was added 4 M hydrogen chloride in EtOAc(15 mL). The reaction mixture was stirred at ambient temperature for 2hr, and concentrated. The residue was alkalized with saturated aqueousNaHCO₃ and the aqueous layer was extracted with CHCl₃ (three times). Thecombined organic layer was dried over MgSO₄, filtered, concentrated. Toa solution of 4-bromo-2-trifluoromethoxy-benzoic acid obtained in step Bof example 13 (331 mg, 1.16 mmol) in CH₂Cl₂ (5 mL) were added DMF (1 μL,0.01 mmol) and SOCl₃ (120 μL, 1.65 mmol). The mixture was stirred atreflux for 30 min and concentrated to give acid chloride as a paleyellow oil. To a suspension ofcis-N²-(4-amino-cyclohexyl)-N-4-methyl-quinazoline-2,4-diamine (300 mg,1.11 mmol) in CH₂Cl₂ (3 mL) was added diisopropylethylamine (410 μL,2.35 mmol). The mixture was cooled on an ice-bath and a solution of theabove residue in CH₂Cl₂ (3 mL) was added dropwise. The reaction mixturewas stirred on an ice-bath for 3.5 hr. The reaction was quenched withsaturated aqueous NaHCO₃ The aqueous layer was extracted with CHCl₃(three times). The combined organic layer was dried over MgSO₄,filtered, concentrated, and purified by flash chromatography (NH-silicagel, 50% EtOAc in hexane) to give a pale yellow solid.

To a solution of the residue (116 mg) in EtOAc (1 mL) was added 4 Mhydrogen chloride in EtOAc (5 mL). The reaction mixture was stirred atambient temperature for 30 min, and concentrated. A solution of theresidue in Et₂O (10 mL) was stirred at ambient temperature for 1 hr andthe precipitate was collected by filtration to give4-bromo-N-[4-(4-methylamino-quinazolin-2-ylamino)-cyclohexyl]-2-trifluoromethoxy-benzamide(102 mg, 16%) as a white solid.

ESI MS m/e 538, M (free)+H⁺; ¹H NMR (300 MHz, CDCl₃) δ 12.72 (s, 1 H),8.66 (d, J=7.1 Hz, 1 H), 8.35 (brs, 1 H), 8.16 (d, J=7.7 Hz, 1 H), 7.74(d, J=8.4 Hz, 1 H), 7.48-7.60 (m, 2 H), 7.40-7.43 (m, 1 H), 7.30 (d,J=8.4 Hz, 1 H), 7.19 (t, J=7.8 Hz, 1 H), 6.57 (d, J=8.1 Hz, 1 H), 4.34(brs, 1 H), 4.15 (brs, 1 H), 3.22 (d, J=3.9 Hz, 3 H), 1.90 (m, 8 H).

Example 54

cis-N-[4-(4-Dimethylamino-quinazolin-2-ylamino)-cyclohexylmethyl]-2-trifluoromethoxy-benzamidehydrochloride

Step A: Synthesis ofcis-N-[4-(4-dimethylamino-quinazolin-2-ylamino)-cyclohexylmethyl]-2-trifluoromethoxy-benzamidehydrochloride.

To a solution ofcis-[4-(4-dimethylamino-quinazolin-2-ylamino)-cyclohexylmethyl]-carbamicacid benzyl ester obtained in step B of example 24 (4.57 g, 10.5 mmol)in MeOH (46 mL) was added 5% Pd/C (460 mg). The mixture was stirred at50° C. under hydrogen atmosphere for 3 days, filtered, and concentratedto give a white solid (3.79 g). To a solution of the above solid (300mg, 1.00 mmol) in CH₂Cl₂ (3 mL) was added triethylamine (280 μL, 2.01mmol). The mixture was cooled on an ice-bath and a solution of2-trifluoromethoxy-benzoyl chloride (236 mg, 1.05 mmol) in CH₂Cl₂ (2 mL)was added dropwise. The reaction mixture was stirred on an ice-bath for5 hr. The reaction was quenched with saturated aqueous NaHCO₃. Theaqueous layer was extracted with CHCl₃ (three times). The combinedorganic layer was dried over MgSO₄, filtered, concentrated, purified byflash chromatography (NH-silica gel, 33% EtOAc in hexane and silica gel,10% MeOH in CHCl₃), and concentrated. To a solution of the residue inEtOAc (1 mL) was added 4 M hydrogen chloride in EtOAc (5 mL). Thereaction mixture was stirred at ambient temperature for 30 min, andconcentrated. A solution of the residue in Et₂O (10 mL) was stirred atambient temperature for 1 hr and the precipitate was collected byfiltration to givecis-N-[4-(4-dimethylamino-quinazolin-2-ylamino)-cyclohexylmethyl]-2-trifluoromethoxy-benzamidehydrochloride (134 mg, 31%) as a white solid.

ESI MS m/e 510, M (free)+Na⁺; ¹H NMR (300 MHz, CDCl₃) δ 13.29 (s, 1 H),8.89 (d, J=7.9 Hz, 1 H), 7.93 (dd, J=7.7, 1.8 Hz, 1 H), 7.89 (d, J=8.4Hz, 1 H), 7.63 (t, J=7.3 Hz, 1 H), 7.52 (d, J=7.9 Hz, 1 H), 7.47 (dd,J=8.1, 1.9 Hz, 1 H), 7.39 (t, J=7.6 Hz, 1 H), 7.29 (d, J=9.0 Hz, 1 H),7.23 (d, J=7.3 Hz, 1 H), 6.77 (t, J=5.6 Hz, 1 H), 4.18-4.36 (m, 1 H),3.51 (s, 6 H), 3.42 (t, J=6.3 Hz, 2 H), 1.35-2.02 (m, 9 H).

Example 55

cis-N-[4-(4-Methylamino-quinazolin-2-ylamino)-cyclohexyl]-2-trifluoromethoxy-benzamidehydrochloride

Step A: Synthesis ofcis-N-[4-(4-methylamino-quinazolin-2-ylamino)-cyclohexyl]-2-trifluoromethoxy-benzamidehydrochloride.

Using the procedure for the step A of example 54, the title compound wasobtained.

ESI MS m/e 460, M (free)+H⁺; ¹H NMR (300 MHz, CDCl₃) δ 12.61 (s, 1 H),8.70 (d, J=4.4 Hz, 1 H), 8.57 (d, J=7.6 Hz, 1 H), 8.26 (d, J=8.1 Hz, 1H), 7.82 (dd, J=7.7, 1.8 Hz, 1 H), 7.08-7.57 (m, 6 H), 6.60 (d, J=8.1Hz, 1 H), 4.25-4.45 (m, 1 H), 4.01-4.25 (m, 1 H), 3.20 (d, J=4.5 Hz, 3H), 1.53-2.18 (m, 8 H).

Example 56

cis-N-[4-(4-Dimethylamino-quinazolin-2-ylamino)-cyclohexyl]-2-trifluoromethoxy-benzamidehydrochloride

Step A: Synthesis ofcis-N-[4-(4-dimethylamino-quinazolin-2-ylamino)-cyclohexyl]-2-trifluoromethoxy-benzamidehydrochloride.

To a suspension of polymer supported DMA (2.45 g, 7.35 mmol) in CH₂Cl₂(6 mL) were added 2-trifluoromethoxy-benzoyl chloride (472 mg, 2.10mmol) andcis-N²-(4-amino-cyclohexyl)-N⁴,N⁴-dimethylquiazoline-2,4-diamineobtained in step C of example 9 (300 mg, 1.05 mmol). The mixture wasstirred at ambient temperature for 24 h, filtered, poured into saturatedaqueous NaHCO₃. The aqueous layer was extracted with CHCl₃ (threetimes). The combined organic layer was dried over MgSO₄, filtered,concentrated, purified by medium-pressure liquid chromatography(NH-silica gel, 25% EtOAc in hexane), and concentrated. To a solution ofthe residue in EtOAc (1 mL) was added 4 M hydrogen chloride in EtOAc (10mL). The reaction mixture was stirred at ambient temperature for 1 hr,and concentrated. A solution of the residue in Et₂O (10 mL) was stirredat ambient temperature for 1 hr and the precipitate was collected byfiltration to givecis-N-[4-(4-dimethylaminoquinazolin-2-ylamino)-cyclohexyl]-2-trifluoromethoxy-benzamidehydrochloride (145 mg, 27%) as a white solid.

ESI MS m/e 474, M+H⁺; ¹H NMR (300 MHz, CDCl₃) δ 13.22 (s, 1 H), 8.88 (d,J=7.5 Hz, 1 H), 7.90 (d, J=8.2 Hz, 1 H), 7.79 (dd, J=7.6, 1.9 Hz, 1 H),7.64 (t, J=7.5 Hz, 1 H), 7.52 (d, J=8.7 Hz, 1 H), 7.47 (dd, J=8.1, 1.9Hz, 1 H), 7.37 (dt, J=7.5, 1.2 Hz, 1 H), 7.20-7.33 (m, 2 H), 6.66 (d,J=8.4 Hz, 1 H), 4.06-4.36 (m, 2 H), 3.52 (s, 6 H), 1.55-2.21 (m, 8 H).

Example 57

cis-N²-[4-(4-Bromo-2-trifluoromethoxy-phenylamino)-cyclohexyl]-N⁴,N⁴-dimethyl-quinazoline-2,4-diaminedihydrochloride

Step A: Synthesis ofcis-N²-[4-(4-bromo-2-trifluoromethoxy-phenylamino)-cyclohexyl]-N⁴,N⁴-dimethyl-quinazoline-2,4-diaminedihydrochloride.

To a glass flask were added 18-crown-6 (647 mg, 2.45 mmol),4-Bromo-1-iodo-2-trifluoromethoxy-benzene (770 mg, 2.10 mmol),cis-N²-(4-amino-cyclohexyl)-N⁴,N⁴-dimethyl-quinazoline-2,4-diamineobtained in step C of example 9 (500 mg, 1.75 mmol), sodiumtert-butoxide (235 mg, 2.45 mmol), tris(dibenzylideneacetone)dipalladium(160 mg, 0.175 mmol),(R)-(+)-2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl (160 mg, 0.175 mmol)and THF (3.5 mL). The reaction mixture was stirred at reflux 18 hr. Themixture was filtered through a pad of celite, concentrated, and purifiedby flash chromatography (NH-silica gel, 33% EtOAc in hexane) to give apale yellow oil. To a solution of above oil in Et₂O (2 mL) was added 4 Mhydrogen chloride in EtOAc (0.3 mL). The mixture was stirred at ambienttemperature for 30 min and concentrated. A solution of the residue inEt₂O (2 mL) was stirred at ambient tempareture for 15 min. Theprecipitate was collected by filtration, washed with Et₂O, and driedunder reduced pressure to givecis-N²-[4-(4-bromo-2-trifluoromethoxy-phenylamino)-cyclohexyl]-N⁴,N⁴-dimethyl-quinazoline-2,4-diaminedihydrochloride (189 mg, 18%) as a white solid.

ESI MS m/e 524, M (free)+H⁺; ¹H NMR (300 MHz, CDCl₃) δ 13.04 (s, 1 H),8.85 (d, J=7.9 Hz, 1 H), 7.90 (d, J=8.1 Hz, 1 H), 7.61-7.70 (m, 1 H),7.53 (d, J=7.6 Hz, 1 H), 7.22-7.31 (m, 1 H), 6.94 (s, 1 H), 6.79 (s, 1H), 6.65 (s, 1 H), 4.28 (brs, 1 H), 3.52 (s, 6 H), 3.30-3.45 (m, 2 H),1.64-2.08 (m, 8 H).

Example 58

cis-N-[4-(4-Methylamino-quinazolin-2-ylamino)-cyclohexylmethyl]-2-trifluoromethoxy-benzamidhydrochloride

Step A: Synthesis ofcis-[4-(4-methylamino-quinazolin-2-ylamino)-cyclohexylmethyl]-carbamicacid benzyl ester.

Using the procedure for the step G of Example 1, the title compound wasobtained.

ESI MS m/e 420, M (free)+H⁺; ¹H NMR (300 MHz, CDCl₃) δ 7.20-7.59 (m, 8H), 7.04 (ddd, J=8.2, 6.8, 1.3 Hz, 1 H), 5.54-5.76 (m, 1 H), 5.10 (s, 2H), 4.78-5.24 (m, 2 H), 4.18-4.36 (m, 1 H), 3.11 (d, J=4.8 Hz, 3 H),2.92-3.16 (m, 2 H), 1.06-1.94 (m, 9 H).

Step B: Synthesis ofcis-N-[4-(4-methylamino-quinazolin-2-ylamino)-cyclohexylmethyl]-2-trifluoromethoxy-benzamidhydrochloride

To a solution ofcis-[4-(4-methylamino-quinazolin-2-ylamino)-cyclohexylmethyl]-carbamicacid benzyl ester (2.73 g, 6.50 mmol) in MeOH (27 mL) was added 10% Pd/C(273 mg). The mixture was stirred at 50° C. under hydrogen atmospherefor 14 hr, filtered, and concentrated to give a colorless solid (1.95g). To a suspension of polymer supported DMAP (2.45 g, 7.35 mmol) inCH₂Cl₂ (10 mL) were added 2-trifluoromethoxy-benzoyl chloride (472 mg,2.10 mmol) and the above solid (300 mg, 1.05 mmol). The mixture wasstirred at ambient temperature for 2.5 days, filtered, poured intosaturated aqueous NaHCO₃. The aqueous layer was extracted with CHCl₃(three times). The combined organic layer was dried over MgSO₄,filtered, concentrated, purified by medium-pressure liquidchromatography (NH-silica gel, 50% EtOAc in hexane) and flashchromatography (silica gel, 20% MeOH in CHCl₃), and concentrated. To asolution of the residue in EtOAc (1 mL) was added 4 M hydrogen chloridein EtOAc (5 mL). The reaction mixture was stirred at ambient temperaturefor 30 min, and concentrated. A solution of the residue in Et₂O (5 mL)was stirred at ambient temperature for 1 hr and the precipitate wascollected by filtration to givecis-N-[4-(4-methylamino-quinazolin-2-ylamino)-cyclohexylmethyl]-2-trifluoromethoxy-benzamidehydrochloride (20 mg, 4%) as a white solid.

ESI MS m/e 474, M+H⁺; ¹H NMR (500 MHz, CDCl₃) δ 12.82 (s, 1 H), 8.63 (d,J=7.3 Hz, 1 H), 7.97-8.12 (m, 2 H), 7.91 (dd, J=7.6, 1.5 Hz, 1 H), 7.54(t, J=7.6 Hz, 1 H), 7.48 (dt, J=7.9, 1.8 Hz, 1 H), 7.38 (t, J=7.0 Hz, 1H), 7.26-7.35 (m, 2 H), 7.19 (t, J=7.6 Hz, 1 H), 6.77 (t, J=5.8 Hz, 1H), 4.30-4.41 (m, 1 H), 3.41 (t, J=6.4 Hz, 2 H), 3.20 (d, J=3.7 Hz, 3H), 1.48-2.01 (m, 9 H).

Example 59

cis-N⁴-Methyl-N²-{4-[(2-trifluoromethoxy-benzylamino)-methyl]-cyclohexyl}-quinazoline-2,4-diaminedihydrochloride

Step A: Synthesis ofcis-N⁴-methyl-N²-{4-[(2-trifluoromethoxy-benzylamino)-methyl]-cyclohexyl}-quinazoline-2,4-diaminedihydrochloride.

To a solution ofcis-[4-(4-methylamino-quinazolin-2-ylamino)-cyclohexylmethyl]-carbamicacid benzyl ester obtained in step A of example 58 (2.73 g, 6.50 mmol)in MeOH (27 mL) was added 10% Pd/C (273 mg). The mixture was stirred at50° C. under hydrogen atmosphere for 14 hr, filtered, and concentratedto give a colorless solid (1.95 g). To a solution of the above solid(300 mg, 1.05 mmol) in MeOH (3 mL) were added2-trifluoromethoxy-benzaldehyde (200 mg, 1.05 mmol), AcOH (63 mg, 1.05mmol), and NaBH₃CN (99 mg, 1.58 mmol). The reaction mixture was stirredat ambient temperature with CaCl₂ tube for 4 hr, poured into 1 M aqueoussodium hydroxide, and the aqueous layer was extracted with CHCl₃ (threetimes). The combined organic layer was dried over MgSO₄, filtered,concentrated, purified by medium-pressure liquid chromatography(NH-silica gel, 50% EtOAc in hexane) and flash chromatography (silicagel, 10% MeOH in CHCl₃), and concentrated. To a solution of the residuein EtOAc (1 mL) was added 4 M hydrogen chloride in EtOAc (5 mL). Thereaction mixture was stirred at ambient temperature for 30 min, andconcentrated. A solution of the residue in Et₂O (10 mL) was stirred atambient temperature for 1 hr and the precipitate was collected byfiltration to givecis-N⁴-methyl-N²-{4-[(2-trifluoromethoxy-benzylamino)-methyl]-cyclohexyl}-quinazoline-2,4-diaminedihydrochloride (175 mg, 33%) as a white solid.

ESI MS m/e 460, M (free)+H⁺; ¹H NMR (300 MHz, CDCl₃) δ 11.49 (brs, 1 H),9.74 (brs, 1 H), 9.57 (d, J=4.4 Hz, 1 H), 8.43 (d, J=8.4 Hz, 1 H), 8.27(d, J=8.4 Hz, 1 H), 8.13 (dd, J=7.5, 1.8 Hz, 1 H), 7.24-7.51 (m, 4 H),6.95-7.16 (m, 2 H), 4.28 (s, 2 H), 4.13-4.38 (m, 1 H), 2.99 (d, J=4.5Hz, 3 H), 2.92 (d, J=4.8 Hz, 2 H), 1.41-2.19 (m, 9 H).

Example 60

cis-N²-{4-[(4-Bromo-2-trifluoromethoxy-benzylamino)-methyl]-cyclohexyl}-N⁴-methyl-quinazoline-2,4-diaminedihydrochloride

Step A: Synthesis ofcis-N²-{4-[(4-bromo-2-trifluoromethoxy-benzylamino)-methyl]-cyclohexyl}-N⁴-methyl-quinazoline-2,4-diaminedihydrochloride.

Using the procedure for the step A of Example 59, the title compound wasobtained.

ESI MS m/e 538, M (free)+H⁺; ¹H NMR (500 MHz, CDCl₃) δ 11.23 (brs, 1 H),9.75 (brs, 2 H), 9.46 (brs, 1 H), 8.43 (d, J=7.9 Hz, 1 H), 8.29 (d,J=8.5 Hz, 1 H), 8.08 (d, J=8.5 Hz, 1 H), 7.55 (dd, J=8.6, 1.8 Hz, 1 H),7.44-7.52 (m, 2 H), 7.14 (t, J=7.3 Hz, 1 H), 7.07 (d, J=7.9 Hz, 1 H),4.24 (s, 2 H), 4.19-4.30 (m, 1 H), 2.88-3.05 (m, 5 H), 1.38-1.84 (m, 9H).

Example 61

cis-4-Bromo-N-[4-(4-methylamino-quinazolin-2-ylamino)-cyclohexylmethyl]-2-trifluoromethoxy-benzamidehydrochloride

Step A: Synthesis ofcis-4-bromo-N-[4-(4-methylamino-quinazolin-2-ylamino)-cyclohexylmethyl]-2-trifluoromethoxy-benzamidehydrochloride.

To a solution ofcis-[4-(4-Methylamino-quinazolin-2-ylamino)-cyclohexylmethyl]-carbamicacid benzyl ester obtained in step A of example 58 (2.73 g, 6.50 mmol)in MeOH (27 mL) was added 10% Pd/C (273 mg). The mixture was stirred at50° C. under hydrogen atmosphere for 14 hr, filtered, and concentratedto givecis-N²-(4-Aminomethyl-cyclohexyl)-N-4-methyl-quinazoline-2,4-diamine(1.95 g) as a white solid. To a solution of4-bromo-2-trifluoromethoxy-benzoic acid obtained in step B of example 13(599 mg, 2.10 mmol) in CH₂Cl₂ (6 mL) was added DMF (1 μL, 14.7 μmol) andSOCl₂ (190 μL, 2.60 mmol). The mixture was stirred at reflux for 30 minand concentrated to give acid chloride as a pale yellow oil. To asuspension of polymer supported DMAP (2.45 g, 7.35 mmol) in CH₂Cl₂ (6mL) were added above acid chloride andcis-N²-(4-aminomethyl-cyclohexyl)-N⁴-methyl-quinazoline-2,4-diamine (300mg). The mixture was stirred at ambient temperature for 24 hr, filtered,poured into saturated aqueous NaHCO₃. The aqueous layer was extractedwith CHCl₃ (three times). The combined organic layer was dried overMgSO₄, filtered, concentrated, purified by medium-pressure liquidchromatography (NH-silica gel, 50% EtOAc in hexane), and concentrated.To a solution of the residue in EtOAc (1 mL) was added 4 M hydrogenchloride in EtOAc (10 mL). The reaction mixture was stirred at ambienttemperature for 1 hr, and concentrated. A solution of the residue inEt₂O (10 mL) was stirred at ambient temperature for 1 hr and theprecipitate was collected by filtration to givecis-4-bromo-N-[4-(4-methylamino-quinazolin-2-ylamino)-cyclohexylmethyl]-2-trifluoromethoxy-benzamidehydrochloride (47 mg, 8%) as a white solid.

ESI MS m/e 551, M (free)⁺; ¹H NMR (500 MHz, CDCl₃) δ 12.61 (s, 1 H),8.56 (d, J=7.3 Hz, 1 H), 8.40 (brs, 1 H), 8.15 (d, J=8.5 Hz, 1 H), 7.78(d, J=8.5 Hz, 1 H), 7.47-7.55 (m, 2 H), 7.42 (t, J=1.5 Hz, 1 H), 7.26(d, J=8.5 Hz, 1 H), 7.17 (t, J=7.6 Hz, 1 H), 6.88 (t, J=5.8 Hz, 1 H),4.32-4.44 (m, 1 H), 3.40 (t, J=6.1 Hz, 2 H), 3.20 (d, J=4.3 Hz, 3 H),1.49-2.00 (m, 8 H).

Example 62

cis-N²-{4-[3-(4-Bromo-2-trifluoromethoxy-phenyl)-propylamino]-cyclohexyl}-N⁴,N⁴-dimethyl-quinazoline-2,4-diaminedihydrochloride

Step A: Synthesis of (E)-3-(4-bromo-2-trifluoromethoxy-phenyl)-acrylicacid ethyl ester.

To a solution of (ethoxy-methoxymethyl-phosphinoyl)-acetic acid ethylester (3.45 g, 15.4 mmol) in THF (230 mL) was added 60% sodium hydridein oil (370 mg, 15.4 mmol). The mixture was stirred at ambienttemperature for 50 min and cooled at 4° C. To the reaction mixture wasadded 4-bromo-2-trifluoromethoxy-benzaldehyde (3 g, 11.2 mmol) in THF(100 mL). The mixture was stirred at ambient temperature for 15 hr. Thesolution was poured into H₂O, and the aqueous layer was extracted withEtOAc (three times). The combined organic layer was dried over MgSO₄,filtered, concentrated, and purified by flash chromatography (silicagel, 5% EtOAc in hexane) to give(E)-3-(4-Bromo-2-trifluoromethoxy-phenyl)-acrylic acid ethyl ester (2.98g, 79%) as a colorless oil.

CI MS m/e 339, M+H⁺; ¹H NMR (300 MHz, CDCl₃) δ 7.85 (d, J=15.8 Hz, 1 H),7.42-7.58 (m, 3 H), 6.48 (d, J=15.8 Hz, 1 H), 4.29 (q, J=7.0 Hz, 2 H),1.35 (t, J=7.0 Hz, 3 H).

Step B: Synthesis of 3-(4-bromo-2-trifluoromethoxy-phenyl)-propan-1-ol.

A suspension of lithium aluminum hydride (834 mg, 22.0 mmol) in Et₂O (20mL) was cooled at 4° C. A solution of(E)-3-(4-bromo-2-trifluoromethoxy-phenyl)-acrylic acid ethyl ester (2.98g, 8.79 mmol) in Et₂O (9 mL) was added dropwise, and the mixture wasstirred at ambient temperature for 90 min. The reaction was quenchedwith EtOAc (6 mL) and saturated aqueous NH₄Cl was added dropwise. Theaqueous layer was extracted with EtOAc (three times). The combinedorganic layer was washed with 1 M aqueous HCl, dried over MgSO₄,filtered, concentrated, and purified by flash chromatography (silicagel, 25% EtOAc in hexane) to give3-(4-bromo-2-trifluoromethoxy-phenyl)-propan-1-ol (1.14 g, 43%) as acolorless oil.

ESI MS m/e 298, M⁺; ¹H NMR (300 MHz, CDCl₃) δ 7.10-7.43 (m, 3 H), 3.68(t, J=6.4 Hz, 2 H), 2.67-2.80 (m, 2 H), 1.75-1.94 (m, 2 H).

Step C: Synthesis of3-(4-bromo-2-trifluoromethoxy-phenyl)-propionaldehyde.

A solution of 3-(4-bromo-2-trifluoromethoxy-phenyl)-propan-1-ol (1.03 g,3.44 mmol) in CH₂Cl₂ (47 mL) was cooled at 4° C. and added celite (1.4g) and pyridinium chlorochromate (1.11 g, 5.16 mmol). The reactionmixture was stirred at ambient temperature for 6 hr and filtered througha pad of celite, concentrated, and purified by flash chromatography(silica gel, 16% EtOAc in hexane) to give3-(4-bromo-2-trifluoromethoxy-phenyl)-propionaldehyde (659 mg, 64%) as acolorless oil.

CI MS m/e 297, M+H⁺; ¹H NMR (300 MHz, CDCl₃) δ 9.80 (t, J=1.1 Hz, 1 H),7.32-7.42 (m, 2 H), 7.17 (d, J=8.4, Hz, 1 H), 2.96 (t, J=7.4 Hz, 2 H),2.72-2.81 (m, 2 H).

Step D: Synthesis ofcis-N²-{4-[3-(4-bromo-2-trifluoromethoxy-phenyl)-propylamino]-cyclohexyl}-N⁴,N⁴-dimethyl-quinazoline-2,4-diaminedihydrochloride.

Using the procedure for the step B of example 37, the title compound wasobtained.

ESI MS m/e 566, M (free)+H⁺; ¹H NMR (300 MHz, CDCl₃) δ 8.81 (d, J=7.2Hz, 1 H), 7.91 (d, J=7.9 Hz, 1 H), 7.60-7.70 (m, 1 H), 7.49 (d, J=8.4Hz, 1 H), 7.12-7.42 (m, 5 H), 4.31 (brs, 1 H), 3.52 (s, 6 H), 3.23 (brs,1 H), 3.02-3.14 (m, 2 H), 2.78 (t, J=7.8 Hz, 2 H), 1.97-2.36 (m, 8 H),1.59-1.85 (m, 2 H).

Example 63

cis-N²-{4-[4-(4-Bromo-2-trifluoromethoxy-phenyl)-butylamino]-cyclohexyl}-N⁴,N⁴-dimethyl-quinazoline-2,4-diaminedihydrochloride

Step A: Synthesis of(E)-4-(4-bromo-2-trifluoromethoxy-phenyl)-but-2-enoic acid ethyl ester.

Using the procedure for the step A of example 62, the title compound wasobtained.

ESI MS m/e 352, N; ¹H NMR (300 MHz, CDCl₃) δ 7.33-7.53 (m, 3 H), 6.64(d, J=16.2 Hz, 1 H), 6.37 (dt, J=16.0, 7.1 Hz, 1 H), 4.18 (q, J=7.2 Hz,2 H), 3.28 (dd, J=7.1, 1.5 Hz, 2 H), 1.29 (t, J=7.2 Hz, 3 H).

Step B: Synthesis of 4-(4-bromo-2-trifluoromethoxy-phenyl)-butan-1-ol.

Using the procedure for the step B of example 62, the title compound wasobtained.

ESI MS m/e 312, M⁺; ¹H NMR (200 MHz, CDCl₃) δ 7.10-7.42 (m, 3 H), 3.68(t, J=5.1 Hz, 2 H), 2.60-2.82 (m, 2 H), 1.50-1.79 (m, 4 H), 1.10-1.50(brs, 1 H).

Step C: Synthesis of4-(4-bromo-2-trifluoromethoxy-phenyl)-butyraldehyde.

Using the procedure for the step C of example 62, the title compound wasobtained.

ESI MS m/e 311, M+H⁺; ¹H NMR (200 MHz, CDCl₃) δ 9.79 (s, 1 H), 7.02-7.22(m, 3 H), 2.60-2.84 (m, 2 H), 2.49 (t, J=5.9 Hz, 2 H), 1.80-2.03 (m, 2H).

Step D: Synthesis ofcis-N²-{4-[4-(4-bromo-2-trifluoromethoxy-phenyl)-butylamino]-cyclohexyl}-N⁴,N⁴-dimethyl-quinazoline-2,4-diaminedihydrochloride.

To a suspension ofcis-N²-(4-amino-cyclohexyl)-N⁴,N⁴-dimethyl-quinazoline-2,4-diamineobtained in step C of example 9 (240 mg, 0.84 mmol) in MeOH (3 mL) wereadded 4-(4-bromo-2-trifluoromethoxy-phenyl)-butyraldehyde (262 mg, 0.84mmol), acetic acid (79 mg, 1.26 mmol), and NaBH₃CN (79 mg, 1.26 mmol).The reaction mixture was stirred at ambient temperature for 8 hr. Thereaction was quenched with saturated aqueous NaHCO₃ The aqueous layerwas extracted with CHCl₃ (three times). The combined organic layer wasdried over MgSO₄, filtered, concentrated, and purified bymedium-pressure liquid chromatography (NH-silica gel, 50% EtOAc inhexane) to give a pale yellow solid. To a solution of above solid inEtOAc (2 mL) was added 4 M hydrogen chloride in EtOAc (10 mL). Themixture was stirred at ambient temperature for 1 hr and concentrated. Asolution of the residue in Et₂O (20 mL) was stirred at ambienttempareture for 1 hr. The solid was collected by filtration, washed withEt₂O, and dried under reduced pressure to givecis-N²-{4-[4-(4-bromo-2-trifluoromethoxy-phenyl)-butylamino]-cyclohexyl}-N⁴,N⁴-dimethyl-quinazoline-2,4-diaminedihydrochloride (220 mg, 40%) as a white solid.

ESI MS m/e 580, M (free)+H⁺; ¹H NMR (200 MHz, CDCl₃) δ 12.73 (brs, 1 H),9.55 (brs, 2 H), 8.66-8.88 (m, 1 H), 7.92 (d, J=7.9 Hz, 1 H), 7.66 (t,J=7.3 Hz, 1 H), 7.48 (d, J=7.7 Hz, 1 H), 7.12-7.40 (m, 3 H), 4.20-4.42(m, 1 H), 3.52 (s, 6 H), 2.92-3.42 (m, 3 H), 2.60-2.78 (m, 2 H),1.58-2.59 (m, 12 H).

Example 64

cis-N²-(4-{[2-(4-Bromo-2-trifluoromethoxy-phenyl)-ethylamino]-methyl}-cyclohexyl)-N⁴,N⁴-dimethyl-quinazoline-2,4-diaminedihydrochloride

Step A: Synthesis ofN²-(4-aminomethyl-cyclohexyl)-N⁴,N⁴-dimethyl-quinazoline-2,4-diamine.

To a solution ofcis-[4-(4-dimethylamino-quinazolin-2-ylamino)-cyclohexylmethyl]-carbamicacid benzyl ester obtained in step B of example 24 (12.1 g, 27.9 mmol)in MeOH (120 mL) was added 10% Pd/C (1.21 g). The mixture was stirred at50° C. under hydrogen atmosphere for 19 hr, filtered, concentrated, andpurified by flash chromatography (NH-silica gel, 66% EtOAc in hexane to15% MeOH in chloroform) to giveN²-(4-aminomethyl-cyclohexyl)-N⁴,N⁴-dimethyl-quinazoline-2,4-diamine(6.9 g, 83%) as a yellow solid.

CI MS m/e 300, M+H⁺; ¹H NMR (300 MHz, CDCl₃) δ 7.81 (d, J=8.4 Hz, 1 H),7.40-7.51 (m, 2 H), 6.98-7.04 (m, 1 H), 5.04 (d, J=7.3 Hz, 1 H),4.24-4.30 (m, 1 H), 3.27 (s, 6 H), 2.60 (d, J=6.4 Hz, 2 H), 1.81-1.96(m, 2 H), 1.57-1.76 (m, 4 H), 0.90-1.51 (m, 5 H).

Step B: Synthesis ofcis-N²-(4-{[2-(4-bromo-2-trifluoromethoxy-phenyl)-ethylamino]-methyl}-cyclohexyl)-N⁴,N⁴-dimethyl-quinazoline-2,4-diaminedihydrochloride.

Using the procedure for the step B of example 37, the title compound wasobtained.

ESI MS m/e 566, M (free)+H⁺; ¹H NMR (300 MHz, CDCl₃) δ 12.45 (s, 1 H),9.74 (brs, 2 H), 8.70 (d, J=7.6 Hz, 1 H), 7.90 (d, J=8.4 Hz, 1 H), 7.66(t, J=7.6 Hz, 1 H), 7.17-7.52 (m, 4 H), 4.30 (brs, 1 H), 3.52 (s, 6 H),3.32-3.50 (m, 2 H), 3.17 (brs, 2 H), 3.01 (brs, 2 H), 1.56-2.10 (m, 9H).

Example 65

cis-N²-(4-{[2-(4-Bromo-2-trifluoromethoxy-phenyl)-ethylamino]-methyl}-cyclohexyl)-N⁴-methyl-quinazoline-2,4-diaminedihydrochloride

Step A: Synthesis ofcis-N²-(4-{[2-(4-bromo-2-trifluoromethoxy-phenyl)-ethylamino]-methyl}-cyclohexyl)-N-4-methyl-quinazoline-2,4-diaminedihydrochloride.

Using the procedure for the step A of example 59, the title compound wasobtained.

ESI MS m/e 552 M (free)+W; ¹H NMR (300 MHz, CDCl₃) δ 11.66 (s, 1 H),9.62 (brs, 1 H), 9.40 (brs, 1 H), 8.05-8.50 (m, 2 H), 7.21-7.58 (m, 4H), 6.96-7.21 (m, 2 H), 4.26 (brs, 1 H), 3.41 (brs, 2 H), 2.75-3.31 (m,7 H), 1.30-2.24 (m, 9 H).

Example 66

cis-N⁴,N⁴-Dimethyl-N²-{4-[2-(2-trifluoromethoxy-phenyl)-ethylamino]-cyclohexyl}-quinazoline-2,4-diaminedihydrochloride

Step A: Synthesis ofcis-N⁴,N⁴-dimethyl-N²-{4-[2-(2-trifluoromethoxy-phenyl)-ethylamino]-cyclohexyl}-quinazoline-2,4-diaminedihydrochloride.

To a solution ofcis-N²-{4-[2-(4-bromo-2-trifluoromethoxy-phenyl)-ethylamino]-cyclohexyl}-N⁴,N⁴-dimethyl-quinazoline-2,4-diaminedihydrochloride obtained in step B of example 37 (250 mg, 0.4 mmol) inEtOH (5 mL) was added 10% Pd/C (75 mg). The mixture was stirred atambient temperature under hydrogen atmosphere for 17 hr, filtered,poured into saturated aqueous NaHCO₃. The aqueous layer was extractedwith CHCl₃ (three times). The combined organic layer was dried overMgSO₄, filtered, concentrated, and purified by flash chromatography(NH-silica gel, 50% EtOAc in hexane) to give a colorless oil. To asolution of above oil in EtOAc (4 mL) was added 4 M hydrogen chloride inEtOAc (0.25 mL). The mixture was stirred at ambient temperature for 1 hrand concentrated. The residue was suspended with Et₂O (15 mL) andstirred at ambient tempareture for 1 hr. The solid was collected byfiltration, washed with Et₂₀, and dried under reduced pressure to givecis-N⁴,N⁴-dimethyl-N²-{4-[2-(2-trifluoromethoxy-phenyl)-ethylamino]-cyclohexyl}-quinazoline-2,4-diaminedihydrochloride (104 mg, 48%) as a white solid.

ESI MS m/e 474, M (free)+H⁺; ¹H NMR (300 MHz, CDCl₃) δ 12.62 (s, 1 H),9.78 (brs, 2 H), 8.71 (brs, 1 H), 7.93 (d, J=8.4 Hz, 1 H), 7.39-7.77 (m,3 H), 7.14-7.37 (m, 4 H), 4.33 (brs, 1 H), 3.15-3.71 (m, 11 H),1.93-2.53 (m, 6 H), 1.62-1.89 (m, 2 H).

Example 67

cis-2-(4-Bromo-2-trifluoromethoxy-phenyl)-N-[4-(4-dimethylamino-quinazolin-2-ylamino)-cyclohexyl]-acetamidehydrochloride

Step A: Synthesis of (4-bromo-2-trifluoromethoxy-phenyl)-acetic acid.

Using the procedure for the step B of example 13, the title compound wasobtained

ESI MS m/e 298, M⁺; ¹H NMR (300 MHz, CDCl₃) δ 7.39-7.47 (m, 2 H), 7.22(d, J=8.1 Hz, 1 H), 3.70 (s, 2 H).

Step B: Synthesis ofcis-2-(4-bromo-2-trifluoromethoxy-phenyl)-N-[4-(4-dimethylamino-quinazolin-2-ylamino)-cyclohexyl]-acetamidehydrochloride.

Using the procedure for the step A of example 47, the title compound wasobtained.

ESI MS m/e 566, M (free)+H⁺; ¹H NMR (300 MHz, CDCl₃) δ 13.15 (s, 1 H),8.91 (d, J=7.7 Hz, 1 H), 7.89 (d, J=8.4 Hz, 1 H), 7.61-7.70 (m, 1 H),7.48-7.56 (m, 1 H), 7.39-7.45 (m, 1 H), 7.21-7.33 (m, 2 H), 6.02 (d,J=8.8 Hz, 1 H), 4.19-4.33 (m, 1 H), 3.82-4.03 (m, 1 H), 3.53 (s, 2 H),3.51 (s, 6 H), 1.64-1.97 (m, 8 H).

Example 68

cis-2-(4-Bromo-2-trifluoromethoxy-phenyl)-N-[4-(4-dimethylamino-quinazolin-2-ylamino)-cyclohexylmethyl]-acetamidehydrochloride

Step A: Synthesis ofcis-2-(4-bromo-2-trifluoromethoxy-phenyl)-N-[4-(4-dimethylamino-quinazolin-2-ylamino)-cyclohexylmethyl]-acetamidehydrochloride.

Using the procedure for the step A of example 47, the title compound wasobtained.

ESI MS m/e 580, M (free)+H⁺; ¹H NMR (300 MHz, CDCl₃) δ 12.85 (brs, 1 H),9.08 (d, J=8.4 Hz, 1 H), 7.90 (d, J=8.8 Hz, 1 H), 7.58-7.72 (m, 1 H),7.19-7.54 (m, 5 H), 6.81-6.98 (m, 1 H), 4.28-4.51 (m, 1 H), 3.83 (s, 2H), 3.51 (s, 6 H), 3.29-3.34 (m, 2 H), 1.42-2.03 (m, 9 H).

Example 69

cis-3-(4-Bromo-2-trifluoromethoxy-phenyl)-N-[4-(4-dimethylamino-quinazolin-2-ylamino)cyclohexyl]-propionamidehydrochloride

Step A: Synthesis of 3-(4-bromo-2-trifluoromethoxy-phenyl)-propionicacid.

To a solution of 3-(4-bromo-2-trifluoromethoxy-phenyl)-propan-1-olobtained in step B of example 62 (1 g, 3.34 mmol) in acetone (15 mL) wasadded Jones reagent (4 mL) at 4° C. The mixture was stirred at ambienttemperature for 2 hr. The solution was poured into water (50 mL), andthe aqueous layer was extracted with Et₂O (three times). The combinedorganic layer was dried over MgSO₄, filtered, concentrated, and purifiedby flash chromatography (silica gel, 25% EtOAc in hexane) to give3-(4-Bromo-2-trifluoromethoxy-phenyl)-propionic acid (930 mg, 89%) as acolorless oil.

ESI MS m/e 313, M⁺; ¹H NMR (200 MHz, CDCl₃) δ 7.31-7.50 (m, 2 H),7.10-7.29 (m, 1 H), 2.97 (t, J=7.7 Hz, 2 H), 2.65 (t, J=7.7 Hz, 2 H).

Step B: Synthesis ofcis-3-(4-bromo-2-trifluoromethoxy-phenyl)-N-[4-(4-dimethylamino-quinazolin-2-ylamino)cyclohexyl]-propionamidehydrochloride.

Using the procedure for the step A of example 47, the title compound wasobtained.

ESI MS m/e 580, M (free)+H⁺; ¹H NMR (300 MHz, CDCl₃) δ 13.12 (brs, 1 H),8.92 (d, J=7.9 Hz, 1 H), 7.90 (d, J=8.3 Hz, 1 H), 7.47-7.73 (m, 2 H),7.15-7.44 (m, 3 H), 5.92 (d, J=8.4 Hz, 1 H), 4.18-4.38 (m, 1 H),3.76-4.03 (m, 1 H), 3.51 (s, 6 H), 2.98 (t, J=7.7 Hz, 2 H), 2.44 (t,J=7.7 Hz, 2 H), 1.55-1.96 (m, 9 H).

Example 70

cis-N-[4-(4-Dimethylamino-quinazolin-2-ylamino)-cyclohexyl]-2-(2-trifluoromethoxy-phenyl)-acetamidehydrochloride

Step A: Synthesis ofcis-N-[4-(4-dimethylamino-quinazolin-2-ylamino)-cyclohexyl]-2-(2-trifluoromethoxy-phenyl)-acetamidehydrochloride.

Using the procedure for the step A of example 47, the title compound wasobtained.

ESI MS m/e 488, M (free)+H⁺; ¹H NMR (300 MHz, CDCl₃) δ 13.20 (s, 1 H),8.84 (d, J=7.6 Hz, 1 H), 7.89 (d, J=8.7 Hz, 1 H), 7.60-7.70 (m, 1H),7.49-7.56 (m, 1 H), 7.20-7.43 (m, 5 H), 5.98 (d, J=7.6 Hz, 1 H), 4.23(brs, 1 H), 3.84-4.03 (m, 1 H), 3.59 (s, 2 H), 3.50 (s, 6 H), 1.62-1.98(m, 8 H).

Example 71

cis-N-[4-(4-Dimethylamino-quinazolin-2-ylamino)-cyclohexylmethyl]-2-(2-trifluoromethoxy-phenyl)-acetamidehydrochloride

Step A: Synthesis ofcis-N-[4-(4-dimethylamino-quinazolin-2-ylamino)-cyclohexylmethyl]-2-(2-trifluoromethoxy-phenyl)-acetamidehydrochloride

Using the procedure for the step A of example 47, the title compound wasobtained.

ESI MS m/e 502, M (free)+H⁺; ¹H NMR (300 MHz, CDCl₃) δ 12.99 (s, 1 H),8.99 (d, J=8.5 Hz, 1 H), 7.90 (d, J=8.2 Hz, 1 H), 7.63 (t, J=7.62 Hz, 1H), 7.38-7.54 (m, 2 H), 7.16-7.34 (m, 4 H), 6.55 (brs, 1 H), 4.28-4.43(m, 1 H), 3.81 (s, 2 H), 3.51 (s, 6 H), 3.27 (s, 2 H), 1.46-1.99 (m, 9H).

Example 72

cis-N⁴,N⁴-Dimethyl-N²-(4-{[2-(2-trifluoromethoxy-phenyl)-ethylamino]-methyl}-cyclohexyl)-quinazoline-2,4-diaminedihydrochloride

Step A:cis-N⁴,N⁴-dimethyl-N²-(4-{[2-(2-trifluoromethoxy-phenyl)-ethylamino]-methyl}-cyclohexyl)-quinazoline-2,4-diaminedihydrochloride

To a solution ofcis-N-[4-(4-dimethylamino-quinazolin-2-ylamino)-cyclohexylmethyl]-2-(2-trifluoromethoxy-phenyl)-acetamide(free) obtained in step A of example 71 (246 mg, 0.5 mmol) in THF (3.5mL) was added 1 M borane-THF complex (2.45 mL, 2.45 mmol). The mixturewas stirred at reflux for 2.5 h, and concentrated. To a solution ofabove residue in THF (3.5 mL) was added 1 M hydrochloric acid (4.41 mL,4.41 mmol). The mixture was stirred at reflux for 1 hr, and cooled toambient temperature. To the reaction mixture was added 2 M aqueoussodium hydroxide, and the aqueous layer was extracted with CHCl₃ (threetimes). The combined organic layer was dried over MgSO₄, filtered,concentrated, and purified by medium-pressure liquid chromatography(NH-silica gel, 50% EtOAc in hexane) to give a colorless oil. To asolution of above oil in EtOAc (4 mL) was added 4 M hydrogen chloride inEtOAc (0.25 mL). The mixture was stirred at ambient temperature for 1 hrand concentrated. A solution of the residue in Et₂O (15 mL) was stirredat ambient tempareture for 1 hr. The precipitate was collected byfiltration, washed with Et₂O, and dried under reduced pressure to givecis-N⁴,N⁴-dimethyl-N²-{4-[2-(2-trifluoromethoxy-phenyl)-ethylamino]-cyclohexyl}-quinazoline-2,4-diaminedihydrochloride (81 mg, 30%) as a white solid.

FAB MS m/e 488, M+H⁺; ¹H NMR (300 MHz, CDCl₃) δ 12.56 (s, 1 H), 9.72(brs, 1 H), 8.72 (d, J=7.7 Hz, 1 H), 7.90 (d, J=8.2 Hz, 1 H), 7.66 (t,J=7.7 Hz, 1 H), 7.42-7.54 (m, 2 H), 7.15-7.32 (m, 4 H), 4.22-4.35 (m, 1H), 3.51 (s, 6 H), 3.38-3.59 (m, 2 H), 3.11-3.30 (m, 2 H), 2.92-3.07 (m,2 H), 2.21 (brs, 1 H), 1.50-2.01 (m, 8 H).

Example 73

cis-N⁴-Methyl-N²-(4-{[2-(2-trifluoromethoxy-phenyl)-ethylamino]-methyl}-cyclohexyl)-quinazoline-2,4-diaminedihydrochloride

Step A: Synthesis ofcis-N⁴-methyl-N³-(4-{[2-(2-trifluoromethoxy-phenyl)-ethylamino]-methyl}-cyclohexyl)-quinazoline-2,4-diaminedihydrochloride.

Using the procedure for the step A of example 66, the title compound wasobtained.

ESI MS m/e 474, M (free)+H⁺; ¹H NMR (200 MHz, CDCl₃) δ 11.72 (s, 1 H),9.23-9.94 (m, 3 H), 8.00-8.66 (m, 2 H), 6.64-7.66 (m, 7 H), 4.26 (brs, 1H), 2.73-3.65 (m, 9 H), 1.27-2.44 (m, 9 H).

Example 74

cis-A-Methyl-N²-{4-[2-(2-trifluoromethoxy-phenyl)-ethylamino]-cyclohexyl}-quinazoline-2,4-diaminedihydrochloride

Step A: Synthesis ofcis-N⁴-methyl-N²-{4-[2-(2-trifluoromethoxy-phenyl)-ethylamino]-cyclohexyl}-quinazoline-2,4-diaminedihydrochloride.

Using the procedure for the step A of example 66, the title compound wasobtained.

ESI MS m/e 460, M (free)+H⁺; ¹H NMR (200 MHz, CDCl₃) δ 12.20 (brs, 1 H),9.84 (brs, 3 H), 8.59-8.79 (m, 1 H), 7.79-8.02 (m, 1 H), 7.10-7.70 (m, 7H), 3.95-4.26 (m, 1 H), 3.09-3.54 (m, 5 H), 2.82-3.03 (m, 3 H),1.57-2.43 (m, 8 H).

Example 75

cis-3-(4-Bromo-2-trifluoromethoxy-phenyl)-N-[4-(4-dimethylamino-quinazolin-2-ylamino)-cyclohexylmethyl]-propionamidehydrochloride

Step A: Synthesis ofcis-3-(4-bromo-2-trifluoromethoxy-phenyl)-N-[4-(4-dimethylamino-quinazolin-2-ylamino)-cyclohexylmethyl]-propionamidehydrochloride.

Using the procedure for the step A of example 47, the title compound wasobtained.

ESI MS m/e 594, M (free)⁺; ¹H NMR (300 MHz, CDCl₃) δ 12.72 (s, 1H), 9.01(d, J=8.7 Hz, 1 H), 7.90 (d, J=8.2 Hz, 1 H), 7.65 (t, J=7.6 Hz, 1 H),7.47 (d, J=7.6 Hz, 1 H), 7.21-7.41 (m, 3 H), 6.96 (brs, 1 H), 4.31-4.44(m, 1 H), 3.51 (s, 6 H), 3.23 -3.35 (m, 2 H), 3.03 (t, J=7.6 Hz, 2 H),2.76 (t, J=7.6 Hz, 2 H), 1.38-1.98 (m, 9 H).

Example 76

cis-N²-(4-{[3-(4-Bromo-2-trifluoromethoxy-phenyl)-propylamino]-methyl}-cyclohexyl)-N⁴,N⁴-dimethyl-quinazoline-2,4-diaminedihydrochloride

Step A: Synthesis ofcis-N²-(4-{[3-(4-bromo-2-trifluoromethoxy-phenyl)-propylamino]-methyl}-cyclohexyl)-N⁴,N⁴-dimethyl-quinazoline-2,4-diaminedihydrochloride.

Using the procedure for the step A of example 72, the title compound wasobtained.

ESI MS m/e 580, M (free)+H⁺; ¹H NMR (200 MHz, CDCl₃) δ 12.56 (s, 1 H),9.40-9.71 (m, 2 H), 8.56-8.76 (m, 1 H), 7.91 (d, J=8.4 Hz, 1 H), 7.66(t, J=7.6 Hz, 1 H), 7.13-7.47 (m, 5 H), 4.17-4.39 (m, 1 H), 3.51 (s, 6H), 2.83-3.16 (m, 4 H), 2.67-2.82 (m, 2 H), 1.38-2.53 (m, 11 H).

Example 77

cis-N²-[4-(4-Amino-2-trifluoromethoxy-benzylamino)-cyclohexyl]-N⁴,N⁴-dimethyl-quinazoline-2,4-diaminetrihydrochloride

Step A: Synthesis ofcis-N²-[4-(4-amino-2-trifluoromethoxy-benzylamino)-cyclohexyl]-N⁴,N⁴-dimethyl-quinazoline-2,4-diaminetrihydrochloride.

To a solution ofcis-N²-[4-(4-bromo-2-trifluoromethoxy-benzylamino)-cyclohexyl]-N⁴,N⁴-dimethyl-quinazoline-2,4-diamineobtained in step A of example 28 (1.5 g, 2.79 mmol) in EtOH (25 mL) wereadded copper powder (443 mg, 6.93 mmol), CuCl (690 mg, 2.79 mmol), and28% aqueous NH₃ (25 mL). The reaction mixture was stirred at reflux for3.5 hr. The mixture was poured into water, and the aqueous layer wasextracted with CHCl₃ (three times). The combined organic layer was driedover MgSO₄, filtered, concentrated, and purified by medium-pressureliquid chromatography (NH-silica gel, 50% EtOAc in hexane) to give acolorless oil. To a solution of above oil in EtOAc (4 mL) was added 4 Mhydrogen chloride in EtOAc (0.25 mL). The mixture was stirred at ambienttemperature for 1 hr and concentrated. A solution of the residue in Et₂O(15 mL) was stirred at ambient tempareture for 1 hr. The precipitate wascollected by filtration, washed with Et₂O, and dried under reducedpressure to givecis-N²-[4-(4-amino-2-trifluoromethoxy-benzylamino)-cyclohexyl]-N⁴,N⁴-dimethyl-quinazoline-2,4-diaminetrihydrochloride (104 mg, 6%) as a white solid.

ESI MS m/e 475, M (free)+H⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 13.08 (brs, 1H), 9.15 (brs, 2 H), 8.32-8.48 (m, 1 H), 8.19 (d, J=8.1 Hz, 1 H),7.73-7.85 (m, 1 H), 7.46 (d, J=8.4 Hz, 1 H), 7.37 (t, J=7.4 Hz, 2 H),6.56-6.71 (m, 2 H), 3.94-4.26 (m, 3 H), 3.49 (s, 6 H), 3.02-3.24 (m, 1H), 1.59-2.09 (m, 8 H).

Example 78

cis-N²-(4-{[3-(4-Bromo-2-trifluoromethoxy-phenyl)-propylamino]-methyl}-cyclohexyl)-N⁴-methyl-quinazoline-2,4-diaminedihydrochloride

Step A: Synthesis ofN²-(4-aminomethyl-cyclohexyl)-N⁴-methyl-quinazoline-2,4-diamine

Using the procedure for the step A of example 64, the title compound wasobtained.

ESI MS m/e 286, M+H⁺; ¹H NMR (300 MHz, CDCl₃) δ 7.35-7.59 (m, 3 H),6.97-7.11 (m, 1 H), 5.59 (brs, 1 H), 5.00-5.18 (m, 1 H), 4.21-4.39 (m, 1H), 3.13 (d, J=4.8 Hz, 3 H), 2.61 (d, J=6.2 Hz, 2 H), 1.57-1.99 (m, 5H),1.04-1.52 (m, 4 H).

Step B: Synthesis ofcis-N²-(4-{[3-(4-bromo-2-trifluoromethoxy-phenyl)-propylamino]-methyl}-cyclohexyl)-N⁴-methyl-quinazoline-2,4-diaminedihydrochloride.

Using the procedure for the step D of example 63, the title compound wasobtained.

ESI MS m/e 566, M (free)+H⁺; ¹H NMR (300 MHz, CDCl₃) δ 11.63 (s, 1 H),9.45 (brs, 3 H), 8.41 (d, J=8.5 Hz, 1 H), 8.32 (d, J=7.9 Hz, 1 H), 7.46(t, J=7.54 Hz, 1 H), 7.24-7.39 (m, 3 H), 6.99-7.17 (m, 2 H), 4.13-4.35(m, 1 H), 2.85-3.12 (m, 7 H), 2.75 (t, J=7.6 Hz, 2 H), 2.27-2.47 (m, 2H), 1.97-2.18 (m, 1 H), 1.37-1.91 (m, 8 H).

Example 79

cis-N²-{4-[3-(4-Bromo-2-trifluoromethoxy-phenyl)-propylamino]-cyclohexyl}-N⁴-methyl-quinazoline-2,4-diaminedihydrochloride

Step A: Synthesis ofcis-N²-{4-[3-(4-bromo-2-trifluoromethoxy-phenyl)-propylamino]-cyclohexyl}-N⁴-methyl-quinazoline-2,4-diaminedihydrochloride

To a suspension ofcis-[4-(4-methylamino-quinazolin-2-ylamino)-cyclohexyl]-carbamic acidtert-butyl ester obtained in step B of example 50 (8.68 g, 23.4 mmol) inCHCl₃ (87 mL) was added 4 M hydrogen chloride in EtOAc (100 mL). Thereaction mixture was stirred at ambient temperature for 2 hr, andconcentrated. The residue was alkalized with saturated aqueous NaHCO₃and the aqueous layer was extracted with CHCl₃ (three times). Thecombined organic layer was dried over MgSO₄, filtered, concentrated(10.57 g). To a suspension of the above residue (594 mg) in MeOH (6 mL)were added 3-(4-bromo-2-trifluoromethoxy-phenyl)-propionaldehydeobtained in step C of example 62 (650 mg, 2.19 mmol), AcOH (132 mg, 2.19mmol), and NaBH₃CN (207 mg, 3.29 mmol). The reaction mixture was stirredat ambient temperature for 16 hr, poured into saturated aqueous NaHCO₃,and the aqueous layer was extracted with CHCl₃ (three times). Thecombined organic layer was dried over MgSO₄, filtered, concentrated,purified by medium-pressure liquid chromatography (NH-silica gel, 50%EtOAc in hexane and silica gel, 16% MeOH in CHCl₃) to give a yellow oil.To a solution of the residue in EtOAc (6 mL) was added 4 M hydrogenchloride in EtOAc (0.14 mL). The reaction mixture was stirred at ambienttemperature for 30 min, and concentrated. A solution of the residue inEt₂O (10 mL) was stirred at ambient temperature for 1 hr and theprecipitate was collected by filtration to givecis-N²-{4-[3-(4-bromo-2-trifluoromethoxy-phenyl)-propylamino]-cyclohexyl}-N⁴-methyl-quinazoline-2,4-diaminedihydrochloride (59 mg, 7%) as a white solid.

ESI MS m/e 552, M (free)+H⁺; ¹H NMR (300 MHz, CDCl₃) δ 12.37 (s, 1 H),9.78 (brs, 1 H), 9.59 (brs, 2 H), 8.68 (d, J=8.2 Hz, 1 H), 7.55-7.67 (m,2 H), 7.27-7.43 (m, 5 H), 3.78-3.96 (m, 1 H), 2.94-3.24 (m, 3 H),2.50-2.89 (m, 5 H), 2.09-2.50 (m, 6 H), 1.60-1.98 (m, 4 H).

Example 80

cis-N²-[4-(4-Chloro-2-trifluoromethoxy-benzylamino)-cyclohexyl]-N⁴,N⁴-dimethyl-quinazoline-2,4-diaminedihydrochloride

Step A: Synthesis ofcis-N²-[4-(4-chloro-2-trifluoromethoxy-benzylamino)-cyclohexyl]-N⁴,N⁴-dimethyl-quinazoline-2,4-diaminedihydrochloride.

A mixture of conc. HCl (420 μL) and NaNO₂ (44 mg, 0.64 mmol) werestirred at 70° C. for 10 min. To the reaction mixture was added asolution ofcis-N²-[4-(4-amino-2-trifluoromethoxy-benzylamino)-cyclohexyl]-N⁴,N⁴-dimethyl-quinazoline-2,4-diamine(free) obtained in step A of example 77 in AcOH (15 mL), and stirred atambient temperature for 10 min. To the reaction mixture was added asolution of CuCl (146 mg, 1.47 mmol) in conc. HCl (1 mL), and stirred at80° C. for 6 hr. The reaction mixture was alkalized with saturatedaqueous NaHCO₃, and the aqueous layer was extracted with CHCl₃ (threetimes). The combined organic layer was dried over MgSO₄, filtered,concentrated, purified by medium-pressure liquid chromatography(NH-silica gel, 50% EtOAc in hexane) to give a yellow oil. To a solutionof above oil in EtOAc (2 mL) was added 4 M hydrogen chloride in EtOAc(10 mL). The mixture was stirred at ambient temperature for 1 hr andconcentrated. A solution of the residue in Et₂O (20 mL) was stirred atambient tempareture for 1 hr. The precipitate was collected byfiltration, washed with Et₂O, and dried under reduced pressure to givecis-N²-[4-(4-chloro-2-trifluoromethoxy-benzylamino)-cyclohexyl]-N⁴,N⁴-dimethyl-quinazoline-2,4-diaminedihydrochloride (70 mg, 29%) as a white solid.

ESI MS m/e 494, M (free)+H⁺; ¹H NMR (300 MHz, CDCl₃) δ 12.66 (s, 1 H),9.82-10.28 (m, 2 H), 8.78 (d, J=7.6 Hz, 1 H), 8.24 (d, J=8.3 Hz, 1 H),7.92 (d, J=8.2 Hz, 1 H), 7.67 (t, J=7.6 Hz, 1 H), 7.47 (d, J=8.1 Hz, 1H), 7.18-7.41 (m, 3 H), 4.20-4.44 (m, 3 H), 3.52 (s, 6 H), 3.23 (brs, 1H), 2.02-2.65 (m, 6 H), 1.75 (t, J=12.8 Hz, 2 H).

Example 81

trans-N²-{4-[(4-Bromo-2-trifluoromethoxy-benzylamino)-methyl]-cyclohexyl}-N⁴,N⁴-dimethyl-quinazoline-2,4-diaminedihydrochloride

Step A: Synthesis ofN²-(4-aminomethyl-cyclohexyl)-N⁴,N⁴-dimethyl-quinazoline-2,4-diamine

To a suspension oftrans-[4-(4-dimethylamino-quinazolin-2-ylamino)-cyclohexylmethyl]-carbamicacid tert-butyl ester obtained in step B of example 6 (400 mg, 1.00mmol) in EtOAc (10 mL) was added 4 M hydrogen chloride in EtOAc (5 mL).The mixture was stirred at ambient temperature for 80 min. The reactionmixture was alkalized with 2 M aqueous sodium hydroxide, and the aqueouslayer was extracted with CHCl₃ (three times). The combined organic layerwas dried over MgSO₄, filtered, concentrated, purified bymedium-pressure liquid chromatography (NH-silica gel, 33% EtOAc inhexane to 3% MeOH in CHCl₃) to giveN²-(4-aminomethyl-cyclohexyl)-N⁴,N⁴-dimethyl-quinazoline-2,4-diamine(250 mg, 83%) as a pale yellow oil.

ESI MS m/e 300, M+H⁺; ¹H NMR (300 MHz, CDCl₃) δ 7.80 (d, J=9.3 Hz, 1 H),7.38-7.53 (m, 2 H), 6.97-7.05 (m, 1 H), 4.77 (d, J=9.3 Hz, 1 H),3.73-4.02 (m, 1 H), 3.26 (s, 6 H), 2.57 (d, J=6.2 Hz, 2 H), 2.13-2.31(m, 2 H), 1.75-1.96 (m, 2 H), 0.92-1.45 (m, 7 H).

Step B: Synthesis oftrans-N²-{4-[(4-bromo-2-trifluoromethoxy-benzylamino)-methyl]-cyclohexyl}-N⁴,N⁴-dimethyl-quinazoline-2,4-diaminedihydrochloride

Using the procedure for the step B of example 37, the title compound wasobtained

ESI MS m/e 552, M (free)+H⁺; ¹H NMR (300 MHz, CDCl₃) δ 12.72 (s, 1 H),10.19 (brs, 2 H), 8.18 (d, J=8.9 Hz, 1 H), 8.06 (d, J=7.9 Hz, 1 H), 7.91(d, J=8.3 Hz, 1 H), 7.42-7.65 (m, 3 H), 7.35 (d, J=8.3 Hz, 1 H), 7.23(t, J=7.5 Hz, 1 H), 4.18-4.29 (m, 2 H), 3.69-3.89 (m, 1 H), 3.52 (s, 6H), 2.64-2.81 (m, 2 H), 1.90-2.24 (m, 5 H), 1.02-1.56 (m, 4 H).

Example 82

trans-N²-[4-(4-Bromo-2-trifluoromethoxy-benzylamino)-cyclohexylmethyl]-N⁴,N⁴-dimethyl-quinazoline-2,4-diaminedihydrochloride

Step A: Synthesis oftrans-N²-(4-amino-cyclohexylmethyl)-N⁴,N⁴-dimethyl-quinazoline-2,4-diamine.

To a solution oftrans-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-cyclohexyl}-carbamicacid benzyl ester obtained in step C of example 3 (330 mg, 0.76 mmol) inMeOH (3.3 mL) was added 10% Pd/C (33 mg). The mixture was stirred atambient temperature under hydrogen atmosphere for 25 hr, filtered,concentrated, and purified by flash chromatography (NH-silica gel, 50%EtOAc in hexane) to givetrans-N²-(4-amino-cyclohexylmethyl)-N⁴,N⁴-dimethyl-quinazoline-2,4-diamine(250 mg, 98%) as a pale yellow oil.

ESI MS m/e 300, M+H⁺; ¹H NMR (300 MHz, CDCl₃) δ 7.80 (d, J=8.1 Hz, 1 H),7.40-7.55 (m, 2 H), 6.95-7.07 (m, 1 H), 4.86-5.02 (m, 1 H), 3.36 (t,J=6.3 Hz, 2 H), 3.26 (s, 6 H), 2.53-2.70 (m, 1 H), 1.77-1.98 (m, 4 H),0.93-1.64 (m, 7 H).

Step B: Synthesis oftrans-N²-[4-(4-bromo-2-trifluoromethoxy-benzylamino)-cyclohexylmethyl]-N⁴,N⁴-dimethyl-quinazoline-2,4-diaminedihydrochloride

Using the procedure for the step B of example 37, the title compound wasobtained.

ESI MS m/e 552, M (free)⁺; ¹H NMR (300 MHz, CDCl₃) δ 13.21 (s, 1 H),10.03 (brs, 2 H), 8.34-8.47 (m, 1 H), 8.07 (d, J=8.4 Hz, 1 H), 7.91 (d,J=8.4 Hz, 1 H), 7.38-7.71 (m, 4 H), 7.20-7.34 (m, 1 H), 4.03-4.20 (m, 2H), 3.51 (s, 6 H), 3.28-3.42 (m, 2 H), 2.65-2.92 (m, 1 H), 2.16-2.35 (m,2 H), 1.86-2.05 (m, 2 H), 1.56-1.83 (m, 3 H), 0.89-1.16 (m, 2 H).

Example 83

cis-N²-[4-(2,2-Diphenyl-ethylamino)-cyclohexyl]-N⁴,N⁴-dimethyl-quinazoline-2,4-diaminedihydrochloride

Step A: Synthesis ofcis-N²-[4-(2,2-diphenyl-ethylamino)-cyclohexyl]-N⁴,N⁴-dimethyl-quinazoline-2,4-diaminedihydrochloride

Using the procedure for the step B of example 37, the title compound wasobtained.

ESI MS m/e 466, M (free)+H⁺; ¹H NMR (300 MHz, CDCl₃) δ 12.60 (brs, 1 H),8.76-9.28 (m, 3 H), 7.91 (d, J=8.3 Hz, 1 H), 7.59-7.71 (m, 2 H),7.14-7.51 (m, 10 H), 5.00 (t, J=7.7 Hz, 1 H), 4.30-4.40 (m, 1 H), 3.72(d, J=7.4 Hz, 2 H), 3.51 (s, 6 H), 3.19-3.43 (m, 1 H), 1.85-2.31 (m, 6H), 1.52-1.76 (s, 2 H).

Example 84

{2-[3-(4-Bromo-2-trifluoromethoxy-benzylamino)-pyrrolidin-1-yl]-quinazolin-4-yl}-dimethyl-aminedihydrochloride

Step A: Synthesis of[2-(3-amino-pyrrolidin-1-yl)-quinazolin-4-yl]-dimethyl-amine.

Using the procedure for the step A of example 81, the title compound wasobtained

ESI MS m/e 258, M+H⁺; ¹H NMR (300 MHz, CDCl₃) δ 7.80 (d, J=8.2 Hz, 1 H),7.41-7.57 (m, 2 H), 6.93-7.06 (m, 1 H), 3.61-4.02 (m, 4 H), 3.40 (dd,J=11.0, 4.97 Hz, 1 H), 3.26 (s, 6 H), 2.09-2.30 (m, 1 H), 1.68-1.87 (m,1 H), 1.22-1.63 (m, 2 H).

Step B: Synthesis of{2-[3-(4-bromo-2-trifluoromethoxy-benzylamino)-pyrrolidin-1-yl]-quinazolin-4-yl}-dimethyl-aminedihydrochloride

Using the procedure for the step B of example 37, the title compound wasobtained.

ESI MS m/e 510, M (free)+H⁺; ¹H NMR (300 MHz, CDCl₃) δ 8.05-8.61 (m, 2H), 7.61-7.96 (m, 2 H), 7.33-7.57 (m, 2 H), 7.17-7.31 (m, 1 H),4.42-4.64 (m, 2 H), 4.34 (s, 2 H), 3.58-4.24 (m, 3 H), 3.46 (s, 6 H),2.81 (brs, 1 H), 2.31-2.60 (m, 1 H).

Example 85

(2-{3-[2-(4-Bromo-2-trifluoromethoxy-phenyl)-ethylamino]-pyrrolidin-1-yl}-quinazolin-4-yl)-dimethyl-aminedihydrochloride

Step A: Synthesis of(2-{3-[2-(4-bromo-2-trifluoromethoxy-phenyl)-ethylamino]-pyrrolidin-1-yl}-quinazolin-4-yl)-dimethyl-aminedihydrochloride

Using the procedure for the step B of example 37, the title compound wasobtained.

ESI MS m/e 524, M (free)⁺; ¹H NMR (300 MHz, CDCl₃) δ 8.15-8.53 (m, 1 H),7.70-7.93 (m, 1 H), 7.62 (t, J=7.6 Hz, 1 H), 7.11-7.46 (m, 4 H),3.60-4.70 (m, 5 H), 3.45 (s, 6 H), 3.04-3.59 (m, 4 H), 2.29-2.98 (m, 2H).

Example 86

N²-[1-(2,2-Diphenyl-ethyl)-piperidin-4-yl]-N⁴,N⁴-dimethyl-quinazoline-2,4-diaminedihydrochloride

Step A: Synthesis ofN²-[1-(2,2-diphenyl-ethyl)-piperidin-4-yl]-N⁴,N⁴-dimethyl-quinazoline-2,4-diaminedihydrochloride

Using the procedure for the step B of example 37, the title compound wasobtained

ESI MS m/e 452, M (free)+H⁺; ¹H NMR (300 MHz, CDCl₃) δ 12.54 (brs, 1 H),12.42 (s, 1 H), 9.82 (d, J=8.4 Hz, 1 H), 7.92 (d, J=8.1 Hz, 1 H),7.66-7.74 (m, 1 H); 7.40-7.54 (m, 5 H), 7.27-7.39 (m, 5 H), 7.14-7.26(m, 2 H), 5.17 (t, J=6.3 Hz, 1 H), 4.39-4.56 (m, 1 H), 3.70-3.87 (m, 2H), 3.34-3.60 (m, 7 H), 3.07-3.25 (m, 2 H), 2.55-2.87 (m, 2 H),1.61-1.94 (m, 4 H).

Example 87

1-[4-(4-Dimethylamino-quinazolin-2-ylamino)-piperidin-1-yl]-3,3-diphenyl-propan-1-onehydrochloride

Step A: Synthesis of1-[4-(4-dimethylamino-quinazolin-2-ylamino)-piperidin-1-yl]-3,3-diphenyl-propan-1-onehydrochloride

Using the procedure for the step A of example 47, the title compound wasobtained.

ESI MS m/e 502, M+Na⁺; ¹H NMR (300 MHz, CDCl₃) δ 13.45 (brs, 1 H), 8.73(d, J=6.9 Hz, 1 H), 7.89 (d, J=8.2 Hz, 1 H), 7.61-7.70 (m, 1 H), 7.56(d, J=7.6 Hz, 1 H), 7.25-7.39 (m, 11 H), 4.67 (t, J=7.5 Hz, 1 H),3.97-4.14 (m, 2 H), 3.70-3.89 (m, 1 H), 3.50 (s, 6 H), 3.13-3.30 (m, 2H), 2.99-3.12 (m, 2 H), 1.31-1.99 (m, 4 H).

Example 88

cis-N-[4-(4-Dimethylamino-quinazolin-2-ylamino)-cyclohexyl]-3,3-diphenyl-propionamidehydrochloride

Step A: Synthesis ofcis-N-[4-(4-dimethylamino-quinazolin-2-ylamino)-cyclohexyl]-3,3-diphenyl-propionamidehydrochloride

Using the procedure for the step A of example 47, the title compound wasobtained.

ESI MS m/e 494, M (free)+H⁺; ¹H NMR (300 MHz, CDCl₃) δ 13.20 (s, 1 H),8.77 (d, J=8.2 Hz, 1 H), 7.88 (d, J=7.7 Hz, 1 H), 7.60-7.69 (m, 1 H),7.53 (d, J=17.1 Hz, 1 H), 7.12-7.33 (m, 11 H), 5.72 (d, J=9.2 Hz, 1 H),4.57 (t, J=8.0 Hz, 1 H), 4.11-4.23 (m, 1 H), 3.72-3.87 (m, 1 H), 3.49(s, 6 H), 2.88 (d, J=7.9 Hz, 2 H), 1.47-1.85 (m, 8 H).

Example 89

(2-{4-[(4-Bromo-2-trifluoromethoxy-benzylamino)-methyl]-piperidin-1-yl}-quinazolin-4-yl)-dimethyl-aminedihydrochloride

Step A: Synthesis of[2-(4-aminomethyl-piperidin-1-yl)-quinazolin-4-yl]-dimethyl-amine

Using the procedure for the step A of example 64, the title compound wasobtained.

ESI MS m/e 286, M+H⁺; ¹H NMR (300 MHz, CDCl₃) δ 7.79 (d, J=8.3 Hz, 1 H),7.42-7.52 (m, 1 H), 7.23-7.36 (m, 1 H), 6.94-7.07 (m, 1 H), 4.94 (d,J=12.7 Hz, 2 H), 3.26 (s, 6 H), 2.74-3.01 (m, 2 H), 2.61 (d, J=6.6 Hz, 2H), 1.46-1.99 (m, 4 H), 1.01-1.39 (m, 3 H).

Step B: Synthesis of(2-{4-[(4-bromo-2-trifluoromethoxy-benzylamino)-methyl]-piperidin-1-yl}-quinazolin-4-yl)-dimethyl-aminedihydrochloride

Using the procedure for the step B of example 37, the title compound wasobtained.

ESI MS m/e 538, M (free)+H⁺; ¹H NMR (300 MHz, CDCl₃) δ 12.66 (s, 1 H),8.50 (d, J=8.1 Hz, 1 H), 8.23 (d, J=8.6 Hz, 1 H), 7.88 (d, J=8.4 Hz, 1H), 7.66 (t, J=7.9 Hz, 1 H), 7.50 (dd, J=8.4, 1.9 Hz, 1 H), 7.36-7.41(m, 1 H), 7.24-7.34 (m, 1 H), 5.01 (brs, 2 H), 4.27 (s, 2 H), 3.49 (s, 6H), 3.05-3.37 (m, 2 H), 2.44-2.92 (m, 3 H), 1.82-2.37 (m, 2 H),1.14-1.62 (m, 2 H).

Example 90

[2-(4-{[2-(4-Bromo-2-trifluoromethoxy-phenyl)-ethylamino]-methyl}-piperidin-1-yl)-quinazolin-4-yl]-dimethyl-aminedihydrochloride

Step A: Synthesis of[2-(4-{[2-(4-bromo-2-trifluoromethoxy-phenyl)-ethylamino]-methyl}-piperidin-1-yl)-quinazolin-4-yl]-dimethyl-aminedihydrochloride.

Using the procedure for the step B of example 37, the title compound wasobtained.

ESI MS m/e 552, M (free)+H; ¹H NMR (300 MHz, CDCl₃) δ 12.63 (s, 1 H),8.48 (d, J=8.2 Hz, 1 H), 7.79-7.97 (d, J=7.5 Hz, 1 H), 7.58-7.73 (m, 1H), 7.19-7.48 (m, 4 H), 5.02 (brs, 2 H), 3.49 (s, 6 H), 2.82-3.69 (m, 6H), 1.98-2.79 (m, 5 H), 1.52 (brs, 2 H).

Example 91

N²-{1-[2-(4-Bromo-2-trifluoromethoxy-phenyl)-ethyl]-piperidin-4-yl}-N⁴,N⁴-dimethyl-quinazoline-2,4-diaminedihydrochloride

Step A: Synthesis ofN²-{1-[2-(4-bromo-2-trifluoromethoxy-phenyl)-ethyl]-piperidin-4-yl}-N⁴,N⁴-dimethyl-quinazoline-2,4-diaminedihydrochloride.

Using the procedure for the step B of example 37, the title compound wasobtained.

ESI MS m/e 538, M (free)+H⁺; ¹H NMR (300 MHz, CDCl₃) δ 12.61 (brs, 1 H),12.43 (s, 1 H), 9.97 (d, J=8.1 Hz, 1 H), 7.94 (d, J=7.9 Hz, 1 H),7.65-7.76 (m, 1 H), 7.28-7.52 (m, 5 H), 4.48-4.62 (m, 1 H), 3.12-3.73(m, 14 H), 2.68-2.92 (m, 2 H), 1.96-2.13 (m, 2 H).

Example 92

N²-[1-(3,3-Diphenyl-propyl)-piperidin-4-yl]-N⁴,N⁴-dimethyl-quinazoline-2,4-diaminedihydrochloride

Step A: Synthesis ofN²-[1-(3,3-diphenyl-propyl)-piperidin-4-yl]-N⁴,N⁴-dimethyl-quinazoline-2,4-diaminedihydrochloride.

Using the procedure for the step A of example 72, the title compound wasobtained.

ESI MS m/e 466, M (free)+H⁺; ¹H NMR (300 MHz, CDCl₃) δ 12.42 (s, 1 H),12.26 (brs, 1 H), 9.87 (d, J=8.2 Hz, 1 H), 7.93 (d, J=8.2 Hz, 1 H),7.65-7.74 (m, 1 H), 7.47 (d, J=8.2 Hz, 1 H), 7.13-7.37 (m, 11 H),4.44-4.60 (m, 1 H), 3.98 (t, J=7.9 Hz, 1 H), 3.28-3.65 (m, 10 H),2.93-3.09 (m, 2 H), 2.63-2.88 (m, 4 H), 1.84-2.02 (m, 2 H).

Example 93

cis-N²-[4-(3,3-Diphenyl-propylamino)-cyclohexyl]-N⁴,N⁴-dimethyl-quinazoline-2,4-diaminedihydrochloride

Step A: Synthesis ofcis-N²-[4-(3,3-diphenyl-propylamino)-cyclohexyl]-N⁴,N⁴-dimethyl-quinazoline-2,4-diaminedihydrochloride.

Using the procedure for the step A of example 72, the title compound wasobtained.

ESI MS m/e 480, M (free)+H⁺; ¹H NMR (300 MHz, CDCl₃) δ 12.58 (s, 1 H),9.53 (s, 2H), 8.58 (d, J=7.9 Hz, 1 H), 7.91 (d, J=8.1 Hz, 1 H), 7.64 (t,J=7.7 Hz, 1 H), 7.48 (d, J=7.9 Hz, 1 H), 7.08-7.33 (m, 11 H), 4.18-4.33(m, 1 H), 4.11 (t, J=7.7 Hz, 1 H), 3.50 (s, 6 H), 3.16 (brs, 1 H), 2.96(brs, 2 H), 2.64-2.84 (m, 2 H), 1.87-2.25 (m, 6 H), 1.53-1.75 (m, 2 H).

Example 94

cis-N²-{4-[(2,2-Diphenyl-ethylamino)-methyl]-cyclohexyl}-N⁴,N⁴-dimethyl-quinazoline-2,4-diaminedihydrochloride

Step A: Synthesis ofcis-N²-{4-[(2,2-diphenyl-ethylamino)-methyl]-cyclohexyl}-N⁴,N⁴-dimethyl-quinazoline-2,4-diaminedihydrochloride

Using the procedure for the step B of example 37, the title compound wasobtained.

ESI MS m/e 480, M (free)+H⁺; ¹H NMR (300 MHz, CDCl₃) δ 12.78 (s, 1 H),8.94 (brs, 2 H), 8.80 (d, J=8.4 Hz, 1 H), 7.89 (d, J=8.1 Hz, 1 H),7.60-7.69 (m, 1 H), 7.44-7.58 (m, 2 H), 7.18-7.42 (m, 9 H), 4.91 (t,J=8.0 Hz, 1 H), 4.19-4.34 (m, 1 H), 3.61-3.76 (m, 2 H), 3.50 (s, 6 H),2.81-2.97 (m, 2 H), 2.04-2.19 (m, 1 H), 1.74-1.91 (m, 2 H), 1.45-1.69(m, 6 H).

Example 95

N²-[1-(4-Bromo-2-trifluoromethoxy-benzyl)-piperidin-4-ylmethyl]-N⁴,N⁴-dimethyl-quinazoline-2,4-diaminedihydrochloride

Step A: Synthesis ofN⁴,N⁴-dimethyl-N²-piperidin-4-ylmethyl-quinazoline-2,4-diamine.

Using the procedure for the step A of example 81, the title compound wasobtained.

ESI MS m/e 408, M+Na⁺; ¹H NMR (300 MHz, CDCl₃) δ 7.82 (d, J=8.3 Hz, 1H), 7.39-7.59 (m, 2 H), 6.96-7.12 (m, 1 H), 4.79-5.11 (m, 1 H),3.94-4.31 (m, 2 H), 3.42 (t, J=5.9 Hz, 2 H), 3.27 (s, 6 H), 2.70 (t,J=12.1 Hz, 2 H), 1.63-1.92 (m, 3 H), 1.46 (s, 9 H), 0.99-1.37 (m, 2 H).

Step B: Synthesis ofN²-[1-(4-bromo-2-trifluoromethoxy-benzyl)-piperidin-4-ylmethyl]-N⁴,N⁴-dimethyl-quinazoline-2,4-diaminedihydrochloride.

Using the procedure for the step B of example 37, the title compound wasobtained.

ESI MS m/e 538, M (free)+H⁺; ¹H NMR (300 MHz, CDCl₃) δ 13.13 (s, 1 H),12.69 (brs, 1 H), 8.73 (t, J=6.3 Hz, 1 H), 8.19 (d, J=8.2 Hz, 1 H), 7.90(d, J=7.6 Hz, 1 H), 7.45-7.73 (m, 4 H), 7.22-7.33 (m, 1 H), 4.10-4.24(m, 2 H), 3.36-3.67 (m, 10 H), 2.61-2.86 (m, 2 H), 1.80-2.33 (m, 5 H).

Example 96

N²-{1-[2-(4-Bromo-2-trifluoromethoxy-phenyl)-ethyl]-piperidin-4-ylmethyl}-N⁴,N⁴-dimethyl-quinazoline-2,4-diaminedihydrochloride

Step A: Synthesis ofN²-{1-[2-(4-bromo-2-trifluoromethoxy-phenyl)-ethyl]-piperidin-4-ylmethyl}-N⁴,N⁴-dimethyl-quinazoline-2,4-diaminedihydrochloride

Using the procedure for the step B of example 37, the title compound wasobtained.

ESI MS m/e 552, M (free)+H⁺; ¹H NMR (300 MHz, CDCl₃) δ 13.16 (brs, 1 H),8.74 (m, 1 H), 7.92 (d, J=8.2 Hz, 1 H), 7.67 (t, J=7.5 Hz, 1 H), 7.53(d, J=7.6 Hz, 1 H), 7.22-7.46 (m, 5 H), 3.44-3.71 (m, 10 H), 3.26-3.39(m, 2 H), 3.01-3.15 (m, 2 H), 2.63-2.86 (m, 2 H), 1.87-2.33 (m, 5 H).

Example 97

N²-[1-(4-Bromo-2-trifluoromethoxy-benzyl)-pyrrolidin-3-yl]-N⁴,N⁴-dimethyl-quinazoline-2,4-diaminedihydrochloride

Step A: Synthesis ofN²-(1-benzyl-pyrrolidin-3-yl)-N⁴,N⁴-dimethyl-quinazoline-2,4-diamine.

A mixture of (2-chloro-quinazolin-4-yl)-dimethyl-amine obtained in stepB of example 1 (5.1 g, 28.9 mmol) and 1-Benzyl-pyrrolidin-3-ylamine (5.1g, 28.9 mmol) in BuOH (8 mL) was stirred at reflux for 26 hr, pouredinto saturated aqueous NaHCO₃, and the aqueous layer was extracted withCHCl₃ (three times). The combined organic layer was dried over MgSO₄,filtered, concentrated, and purified by flash chromatography (NH-silicagel, 10% to 16% EtOAc in hexane) to giveN²-(1-benzyl-pyrrolidin-3-yl)-N⁴,N⁴-dimethyl-quinazoline-2,4-diamine(3.37 g, 50%) as a pale yellow solid.

ESI MS m/e 348, M+H⁺; ¹H NMR (300 MHz, CDCl₃) δ 7.80 (d, J=9.0 Hz, 1 H),7.46 (m, 2 H), 7.18-7.38 (m, 5 H), 7.02 (ddd, J=8.3, 6.3, 1.9 Hz, 1 H),5.30 (brs, 1 H), 4.59-4.75 (m, 1 H), 3.63 (d, J=2.5 Hz, 2 H), 3.25 (s, 6H), 2.88 (dd, J=9.6, 6.6 Hz, 1 H), 2.70-2.81 (m, 1 H), 2.28-2.60 (m, 3H), 1.64-1.78 (m, 1 H).

Step B: Synthesis ofN⁴,N⁴-dimethyl-N²-pyrrolidin-3-yl-quinazoline-2,4-diamine.

To a solution ofN²-(1-benzyl-pyrrolidin-3-yl)-N⁴,N⁴-dimethyl-quinazoline-2,4-diamine(3.3 g, 9.5 mmol) in MeOH (33 mL) was added Pd(OH)₂ (660 mg). Themixture was stirred at ambient temperature under hydrogen atmosphere for13 hr, and stirred at 50° C. for 6 hr. The mixture was filtered,concentrated, and purified by medium-pressure liquid chromatography(NH-silica gel, 1% to 3% MeOH in CHCl₃) to giveN⁴,N⁴-dimethyl-N²-pyrrolidin-3-yl-quinazoline-2,4-diamine (2.3 g, 93%)as a yellow oil.

ESI MS m/e 258, M+H⁺; ¹H NMR (300 MHz, CDCl₃) δ 7.82 (d, J=7.8 Hz, 1 H),7.42-7.54 (m, 2 H), 7.03 (ddd, J=8.3, 6.4, 1.8 Hz, 1 H), 5.03 (brs, 1H), 4.52 (brs, 1 H), 3.26 (s, 6 H), 2.83-3.24 (m, 4 H), 1.97-2.30 (m, 2H), 1.57-1.77 (m, 1 H).

Step C: Synthesis ofN²-[1-(4-bromo-2-trifluoromethoxy-benzyl)-pyrrolidin-3-yl]-N⁴,N⁴-dimethyl-quinazoline-2,4-diaminedihydrochloride

Using the procedure for the step B of example 37, the title compound wasobtained.

ESI MS m/e 510, M (free)+H⁺; ¹H NMR (300 MHz, CDCl₃) δ 13.22 (brs, 1 H),12.87 (s, 1 H), 9.68 (d, J=7.4 Hz, 1 H), 8.11 (d, J=8.4 Hz, 1 H), 7.95(d, J=8.4 Hz, 1 H), 7.71 (t, J=8.3 Hz, 1 H), 7.43-7.63 (m, 3 H),7.28-7.38 (m, 1 H), 4.94-5.15 (m, 1 H), 4.41 (s, 2 H), 4.00-4.17 (m, 1H), 3.26-3.82 (m, 8 H), 3.00-3.16 (m, 1 H), 2.59-2.82 (m, 1 H),2.18-2.37 (m, 1 H).

Example 98

N²-{1-[2-(4-Bromo-2-trifluoromethoxy-phenyl)-ethyl]-pyrrolidin-3-yl}-N⁴,N⁴-dimethyl-quinazoline-2,4-diaminedihydrochloride

Step A: Synthesis ofN²-{1-[2-(4-bromo-2-trifluoromethoxy-phenyl)-ethyl]-pyrrolidin-3-yl}-N⁴,N⁴-dimethyl-quinazoline-2,4-diaminedihydrochloride.

Using the procedure for the step B of example 37, the title compound wasobtained.

ESI MS m/e 524, M (free)+H⁺; ¹H NMR (300 MHz, CDCl₃) δ 9.61-9.78 (m, 1H), 7.96 (d, J=8.4 Hz, 1 H), 7.71 (t, J=7.7 Hz, 1 H), 7.55 (d, J=8.2 Hz,1 H), 7.29-7.47 (m, 4 H), 4.89-5.12 (m, 1 H), 4.07-4.28 (m, 1 H),2.99-3.97 (m, 13 H), 2.55-2.79 (m, 1 H), 2.22-2.42 (m, 1 H).

Example 99

1-(4-Bromo-2-trifluoromethoxy-phenyl)-1-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-piperidin-1-yl}-methanonehydrochloride

Step A: Synthesis of1-(4-bromo-2-trifluoromethoxy-phenyl)-1-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-piperidin-1-yl}-methanonehydrochloride.

Using the procedure for the step A of example 47, the title compound wasobtained.

ESI MS m/e 552, M (free)+H⁺; ¹H NMR (300 MHz, CDCl₃) δ 13.44 (brs, 1 H),8.53-8.77 (m, 1 H), 7.90 (d, J=8.5 Hz, 1 H), 7.66 (t, J=7.7 Hz, 1 H),7.43-7.61 (m, 3 H), 7.19-7.37 (m, 1 H), 4.69-4.85 (m, 1 H), 3.20-3.63(m, 10 H), 2.61-3.13 (m, 2 H), 1.76-2.14 (m, 3 H), 1.08-1.48 (m, 2 H).

Example 100

cis-3-(3,4-Difluoro-phenyl)-N-[4-(4-dimethylamino-quinazolin-2-ylamino)-cyclohexyl]-propionamidehydrochloride

Step A: Synthesis ofcis-3-(3,4-difluoro-phenyl)-N-[4-(4-dimethylamino-quinazolin-2-ylamino)-cyclohexyl]-propionamidehydrochloride.

Using the procedure for the step A of example 47, the title compound wasobtained.

ESI MS m/e 454, M (free)+H⁺; ¹H NMR (300 MHz, CDCl₃) δ 13.05 (s, 1 H),8.87 (d, J=8.1 Hz, 1 H), 7.89 (d, J=8.2 Hz, 1 H), 7.65 (t, J=7.7 Hz, 1H), 7.51 (d, J=7.3 Hz, 1H), 7.20-7.27 (m, 1 H), 6.88-7.09 (m, 3 H), 5.97(d, J=8.5 Hz, 1 H), 4.26 (brs, 1 H), 3.91 (brs, 1 H), 3.51 (s, 6 H),2.92 (t, J=7.6 Hz, 2 H), 2.44 (t, J=7.6 Hz, 2 H), 1.61-1.93 (brs, 8 H).

Example 101

cis-N²-{4-[3-(3,4-Difluoro-phenyl)-propylamino]-cyclohexyl}-N⁴,N⁴-dimethyl-quinazoline-2,4-diaminedihydrochloride

Step A: Synthesis ofcis-N²-{4-[3-(3,4-difluoro-phenyl)-propylamino]-cyclohexyl}-N⁴,N⁴-dimethyl-quinazoline-2,4-diaminedihydrochloride.

Using the procedure for the step A of example 72, the title compound wasobtained.

ESI MS m/e 440, M (free)+H⁺; ¹H NMR (300 MHz, CDCl₃) δ 12.62 (s, 1 H),9.54 (s, 2 H), 8.72 (d, J=7.6 Hz, 1 H), 7.91 (d, J=8.4 Hz, 1 H),7.62-7.70 (m, 1 H), 7.48 (d, J=7.6 Hz, 1 H), 7.24-7.33 (m, 1 H),6.90-7.06 (m, 3 H), 4.29 (brs, 1 H), 3.52 (s, 6 H), 3.00-3.42 (m, 3 H),2.67-2.81 (m, 2 H), 1.93-2.43 (m, 8 H), 1.60-1.80 (m, 2 H).

Example 102

trans-4-Bromo-N-[4-(4-dimethylamino-quinazolin-2-ylamino)-cyclohexylmethyl]-2-trifluoromethoxy-benzamidehydrochloride

Step A: Synthesis ofN²-(4-aminomethyl-cyclohexyl)-N⁴,N⁴-dimethyl-quinazoline-2,4-diamine.

Using the procedure for the step A of example 81, the title compound wasobtained.

ESI MS m/e 300, M+H⁺; ¹H NMR (300 MHz, CDCl₃) δ 7.79 (d, J=8.4 Hz, 1 H),7.45 (m, 2 H), 7.00 (ddd, J=8.4, 6.3, 1.9 Hz, 1 H), 4.80 (d, J=8.2 Hz, 1H), 3.82-3.94 (m, 1 H), 3.24 (s, 6 H), 2.56 (d, J=6.2 Hz, 2 H),2.14-2.28 (m, 2 H), 1.78-1.92 (m, 2 H), 0.95-1.42 (m, 7 H).

Step B: Synthesis oftrans-4-bromo-N-[4-(4-dimethylamino-quinazolin-2-ylamino)-cyclohexylmethyl]-2-trifluoromethoxy-benzamidehydrochloride.

Using the procedure for the step A of example 47, the title compound wasobtained.

ESI MS m/e 566, M+H⁺; ¹H NMR (300 MHz, CDCl₃) δ 13.48 (s, 1 H), 8.34 (d,J=7.5 Hz, 1 H), 7.83-7.94 (m, 2 H), 7.43-7.69 (m, 4 H), 7.20-7.29 (m, 1H), 6.49-6.62 (m, 1 H), 3.72-3.93 (m, 1 H), 3.50 (s, 6 H), 3.39 (t,J=6.3 Hz, 2 H), 2.09-2.22 (m, 2 H), 1.85-1.98 (m, 2 H), 1.37-1.69 (m, 3H), 1.08-1.28 (m, 2 H).

Example 103

4-Bromo-N-[1-(4-dimethylamino-quinazolin-2-yl)-piperidin-4-ylmethyl]-2-trifluoromethoxy-benzamidehydrochloride

Step A: Synthesis of4-bromo-N-[1-(4-dimethylamino-quinazolin-2-yl)-piperidin-4-ylmethyl]-2-trifluoromethoxy-benzamidehydrochloride.

Using the procedure for the step A of example 47, the title compound wasobtained.

ESI MS m/e 552, M (free)⁺; ¹H NMR (300 MHz, CDCl₃) δ 13.50 (s, 1 H),8.73 (d, J=8.5 Hz, 1 H), 7.86 (d, J=8.4 Hz, 1 H), 7.81 (d, J=8.4 Hz, 1H), 7.62-7.71 (m, 1 H), 7.53 (dd, J=8.4, 1.87 Hz, 1 H), 7.45 (s, 1 H),7.23-7.32 (m, 1 H), 6.77-6.87 (m, 1 H), 3.30-3.55 (m, 10 H), 2.96-3.27(m, 2 H), 1.89-2.15 (m, 3 H), 1.28-1.57 (m, 2 H).

Example 104

cis-2-(3,4-Difluoro-phenyl)-N-[4-(4-dimethylamino-quinazolin-2-ylamino)-cyclohexylmethyl]-acetamidehydrochloride

Step A: Synthesis ofcis-2-(3,4-difluoro-phenyl)-N-[4-(4-dimethylamino-quinazolin-2-ylamino)-cyclohexylmethyl]-acetamidehydrochloride

Using the procedure for the step A of example 47, the title compound wasobtained.

ESI MS m/e 454, M (free)+H⁺; ¹H NMR (300 MHz, CDCl₃) δ 12.66 (s, 1 H),9.08 (d, J=8.9 Hz, 1 H), 7.90 (d, J=8.1 Hz, 1 H), 7.66 (ddd, J=8.4, 7.2,1.2 Hz, 1 H), 7.48 (dd, J=8.4, 0.9 Hz, 1 H), 7.32-7.41 (m, 1 H),7.12-7.31 (m, 3 H), 6.97-7.08 (m, 1 H), 4.35-4.48 (m, 1 H), 3.78 (s, 2H), 3.52 (s, 6 H), 3.28-3.36 (m, 2 H), 1.42-2.05 (m, 9 H).

Example 105

cis-N²-[4-(4-Dimethylamino-quinazolin-2-ylamino)-cyclohexylmethyl]-3,4-difluoro-benzamidehydrochloride

Step A: Synthesis ofcis-N-[4-(4-dimethylamino-quinazolin-2-ylamino)-cyclohexylmethyl]-3,4-difluoro-benzamidehydrochloride.

Using the procedure for the step A of example 47, the title compound wasobtained.

ESI MS m/e 440, M (free)+H⁺; ¹H NMR (300 MHz, CDCl₃) δ 12.89 (s, 1 H),9.11 (d, J=8.2 Hz, 1 H), 7.88 (m, 3 H), 7.64 (ddd, J=8.4, 7.2, 1.2 Hz, 1H), 7.49 (dd, J=8.4, 0.9 Hz, 1 H), 7.18-7.29 (m, 2 H), 6.96-7.07 (m, 1H), 4.29-4.44 (m, 1 H), 3.51 (s, 8 H), 1.55-2.02(m, 9 H).

Example 106

cis-N²-(4-{[2-(3,4-Difluoro-phenyl)-ethylamino]-methyl}-cyclohexyl)-N⁴,N⁴-dimethyl-quinazoline-2,4-diaminedihydrochloride

Step A: Synthesis ofcis-N²-(4-{[2-(3,4-difluoro-phenyl)-ethylamino]-methyl}-cyclohexyl)-N⁴,N⁴-dimethyl-quinazoline-2,4-diaminedihydrochloride.

Using the procedure for the step A of example 72, the title compound wasobtained.

ESI MS m/e 440, M (free)+H⁺; ¹H NMR (300 MHz, CDCl₃) δ 12.43 (s, 1 H),9.64 (brs, 2 H), 8.66 (d, J=8.3 Hz, 1 H), 7.91 (d, J=8.3 Hz, 1 H), 7.67(t, J=7.8 Hz, 1 H), 7.46 (d, J=8.3 Hz, 1 H), 7.28 (t, J=7.8 Hz, 1 H),6.97-7.17 (m, 3 H), 4.24-4.37 (m, 1 H), 3.52 (s, 6 H), 3.30-3.44 (m, 2H), 2.94-3.25 (m, 4 H), 1.57-2.28 (m, 9 H).

Example 107

cis-N²-{4-[(3,4-Difluoro-benzylamino)-methyl]-cyclohexyl}-N⁴,N⁴-dimethyl-quinazoline-2,4-diaminedihydrochloride

Step A: Synthesis ofcis-N²-{4-[(3,4-difluoro-benzylamino)-methyl]-cyclohexyl}-N⁴,N⁴-dimethyl-quinazoline-2,4-diaminedihydrochloride

Using the procedure for the step A of example 72, the title compound wasobtained.

ESI MS m/e 426, M (free)+H⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 9.39 (s, 2 H),8.44 (m, 1 H), 8.17 (d, J=8.4 Hz, 1 H), 7.72-7.88 (m, 2 H), 7.27-7.61(m, 4 H), 4.11-4.31 (m, 3 H), 3.48 (s, 6 H), 2.81 (d, J=6.1 Hz, 2 H),1.32-2.03 (m, 9 H).

Example 108

2-(4-Bromo-2-trifluoromethoxy-phenyl)-1-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-piperidin-1-yl}-ethanonehydrochloride

Step A: Synthesis of2-(4-bromo-2-trifluoromethoxy-phenyl)-1-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-piperidin-1-yl}-ethanonehydrochloride.

Using the procedure for the step A of example 47, the title compound wasobtained.

ESI MS m/e 566, M (free)+H⁺; ¹H NMR (300 MHz, CDCl₃) δ 13.48 (s, 1 H),8.65 (t, J=5.8 Hz, 1 H), 7.90 (d, J=8.4 Hz, 1 H), 7.53-7.70 (m, 2 H),7.37-7.44 (m, 2 H), 7.20-7.32 (m, 2 H), 4.59-4.72 (m, 1 H), 3.80-3.94(m, 1 H), 3.68 (d, J=6.1 Hz, 2 H), 3.25-3.58 (m, 8 H), 2.94-3.12 (m, 1H), 2.50-2.68 (m, 1 H), 1.75-2.03 (m, 3 H), 1.06-1.32 (m, 2 H).

Example 109

trans-2-(4-Bromo-2-trifluoromethoxy-phenyl)-N-[4-(4-dimethylamino-quinazolin-2-ylamino)-cyclohexylmethyl]-acetamide

Step A: Synthesis oftrans-2-(4-bromo-2-trifluoromethoxy-phenyl)-N-[4-(4-dimethylamino-quinazolin-2-ylamino)-cyclohexylmethyl]-acetamide.

Using the procedure for the step A of example 47, the title compound wasobtained.

ESI MS m/e 580, M (free)⁺; ¹H NMR (300 MHz, CDCl₃) δ 8.28 (d, J=6.7 Hz,1 H), 7.87-7.90 (d, J=8.5 Hz, 1 H), 7.52-7.66 (m, 2 H), 7.39-7.44 (m, 2H), 7.20-7.33 (m, 2 H), 5.85-5.98 (m, 1 H), 3.70-3.91 (m, 1 H), 3.58 (s,2 H), 3.50 (s, 6 H), 3.16 (t, J=6.5 Hz, 2 H), 2.03-2.20 (m, 2 H),1.28-1.88 (m, 5 H), 0.96-1.18 (m, 2 H).

Example 110

cis-N-[4-(4-Dimethylamino-quinazolin-2-ylamino)-cyclohexyl]-3,4-difluoro-benzamidehydrochloride

Step A: Synthesis ofcis-N-[4-(4-dimethylamino-quinazolin-2-ylamino)-cyclohexyl]-3,4-difluoro-benzamidehydrochloride.

Using the procedure for the step A of example 47, the title compound wasobtained.

ESI MS m/e 448, M (free)+Na⁺; ¹H NMR (300 MHz, CDCl₃) δ 13.01 (s, 1 H),8.96 (d, J=8.1 Hz, 1 H), 7.91 (d, J=8.2 Hz, 1 H), 7.55-7.79 (m, 4 H),7.49-7.54 (m, 1 H), 7.15-7.32 (m, 2 H), 6.76 (d, J=8.4 Hz, 1 H),4.30-4.41 (m, 1 H), 4.03-4.22 (m, 1 H), 3.52 (s, 6 H), 1.67-2.07 (m, 8H).

Example 111

cis-3-(3,4-Difluoro-phenyl)-N-[4-(4-dimethylamino-quinazolin-2-ylamino)-cyclohexylmethyl]-propionamidehydrochloride

Step A: Synthesis ofcis-3-(3,4-difluoro-phenyl)-N-[4-(4-dimethylamino-quinazolin-2-ylamino)-cyclohexylmethyl]-propionamidehydrochloride.

Using the procedure for the step A of example 47, the title compound wasobtained.

ESI MS m/e 468, M (free)+H⁺; ¹H NMR (300 MHz, CDCl₃) δ 12.70 (s, 1 H),9.00 (d, J=8.3 Hz, 1 H), 7.90 (d, J=8.3 Hz, 1 H), 7.66 (ddd, J=8.3, 7.2,1.0 Hz, 1 H), 7.48 (dd, J=8.3, 1.0 Hz, 1 H), 7.11-7.31 (m, 2 H),6.84-7.06 (m, 3 H), 4.32-4.44 (m, 1 H), 3.51 (s, 6H), 3.26-3.33 (m, 2H), 2.96 (t, J=7.5 Hz, 2 H), 2.76 (t, J=7.4 Hz, 2 H), 1.34-1.94 (m, 9H).

Example 112

cis-N²-[4-(3,4-Difluoro-benzylamino)-cyclohexyl]-N⁴,N⁴-dimethyl-quinazoline-2,4-diaminedihydrochloride

Step A: Synthesis ofcis-N²-[4-(3,4-difluoro-benzylamino)-cyclohexyl]-N⁴,N⁴-dimethyl-quinazoline-2,4-diaminedihydrochloride.

Using the procedure for the step A of example 72, the title compound wasobtained.

ESI MS m/e 434, M (free)+Na⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 13.03 (s, 1H), 9.50 (brs, 2 H), 8.31-8.40 (m, 1 H), 8.19 (d, J=8.2 Hz, 1 H),7.73-7.90 (m, 2 H), 7.29-7.60 (m, 4 H), 4.04-4.28 (m, 3 H), 3.46 (s, 6H), 3.06-3.22 (m, 1 H), 1.61-2.10 (m, 8 H).

Example 113

cis-N²-(4-{[3-(3,4-Difluoro-phenyl)-propylamino]-methyl}-cyclohexyl)-N⁴,N⁴-dimethyl-quinazoline-2,4-diaminedihydrochloride

Step A: Synthesis ofcis-N²-(4-{[3-(3,4-difluoro-phenyl)-propylamino]-methyl}-cyclohexyl)-N⁴,N⁴-dimethyl-quinazoline-2,4-diaminedihydrochloride.

Using the procedure for the step A of example 72, the title compound wasobtained.

ESI MS m/e 454, M (free)+H⁺; ¹H NMR (300 MHz, CDCl₃) δ 12.50 (s, 1 H),9.43 (brs, 2 H), 8.60 (d, J=7.93 Hz, 1 H), 7.90 (d, J=8.2 Hz, 1 H), 7.65(ddd, J=8.2, 7.2, 1.1 Hz, 1 H), 7.46 (d, J=8.6 Hz, 1 H), 7.23-7.30 (m, 1H), 6.91-7.08 (m, 3 H), 4.22-4.34 (m, 1 H), 3.51 (s, 6 H), 2.87-3.07 (m,4 H), 2.68 (t, J=7.7 Hz, 2 H), 1.53-2.43 (m, 11 H).

Example 114

2-(4-Bromo-2-trifluoromethoxy-phenyl)-N-[1-(4-dimethylamino-quinazolin-2-yl)-piperidin-4-ylmethyl]-acetamidehydrochloride

Step A: Synthesis of2-(4-bromo-2-trifluoromethoxy-phenyl)-N-[1-(4-dimethylamino-quinazolin-2-yl)-piperidin-4-ylmethyl]-acetamidehydrochloride

Using the procedure for the step A of example 47, the title compound wasobtained.

ESI MS m/e 588, M (free)+Na⁺; ¹H NMR (300 MHz, CDCl₃) δ 13.32 (s, 1 H),8.68 (d, J=8.4 Hz, 1 H), 7.86 (d, J=7.4 Hz, 1 H), 7.65 (ddd, J=8.4, 7.1,1.2 Hz, 1 H), 7.23-7.42 (m, 4 H), 6.59-6.69 (m, 1 H), 3.60 (s, 2 H),3.48 (s, 7 H), 2.90-3.37 (m, 5 H), 1.78-2.08 (m, 3 H), 1.19-1.46 (m, 2H).

Example 115

trans-2-(4-Bromo-2-trifluoromethoxphenyl)-N-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-cyclohexylmethyl}-acetamidehydrochloride

Step A: Synthesis oftarns-2-(4-bromo-2-trifluoromethoxy-phenyl)-N-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-cyclohexylmethyl}-acetamidehydrochloride.

Using the procedure for the step A of example 47, the title compound wasobtained.

ESI MS m/e 616, M (free)+Na⁺; ¹H NMR (300 MHz, CDCl₃) δ 8.37-8.49 (m, 1H), 7.89 (d, J=8.5 Hz, 1 H), 7.53-7.68 (m, 2 H), 7.40-7.45 (m, 2 H),7.20-7.32 (m, 2 H), 5.60-5.71 (m, 1 H), 3.55 (s, 2 H), 3.50 (s, 6 H),3.35 (t, J=6.1 Hz, 2 H), 3.08 (t, J=6.4 Hz, 2 H), 0.77-2.00 (m, 10 H).

Example 116

cis-2-(3,4-Difluoro-phenyl)-N-[4-(4-dimethylamino-quinazolin-2-ylamino)-cyclohexyl]-acetamidehydrochloride

Step A: Synthesis ofcis-2-(3,4-difluoro-phenyl)-N-[4-(4-dimethylamino-quinazolin-2-ylamino)-cyclohexyl]-acetamidehydrochloride

Using the procedure for the step A of example 47, the title compound wasobtained.

ESI MS m/e 440, M (free)+H⁺; ¹H NMR (300 MHz, CDCl₃) δ 13.01 (s, 1 H),8.85 (d, J=8.2 Hz, 1 H), 7.89 (d, J=8.2 Hz, 1 H), 7.65 (ddd, J=8.2, 7.1,1.2 Hz, 1 H), 7.52 (d, J=8.2 Hz, 1 H), 6.95-7.33 (m, 4 H), 6.32 (d,J=7.6 Hz, 1 H), 4.19-4.34 (m, 1 H), 3.82-4.01 (m, 1 H), 3.51 (s, 6 H),3.47 (s, 2 H), 1.61-2.01 (m, 8 H).

Example 117

cis-N²-{4-[2-(3,4-Difluoro-phenyl)-ethylamino]-cyclohexyl}-N⁴,N⁴-dimethyl-quinazoline-2,4-diaminedihydrochloride

Step A: Synthesis ofcis-N²-{4-[2-(3,4-difluoro-phenyl)-ethylamino]-cyclohexyl}-N⁴,N⁴-dimethyl-quinazoline-2,4-diaminedihydrochloride.

Using the procedure for the step A of example 72, the title compound wasobtained.

ESI MS m/e 426, M (free)+H⁺; ¹H NMR (300 MHz, CDCl₃) δ 12.51 (s, 1 H),9.70 (brs, 2 H), 8.67 (d, J=7.5 Hz, 1 H), 7.92 (d, J=8.0 Hz, 1 H), 7.68(t, J=8.0 Hz, 1 H), 7.52 (d, J=8.4 Hz, 1 H), 7.30 (t, J=7.8 Hz, 1 H),6.97-7.22 (m, 3 H), 4.34 (brs, 1 H), 3.53 (s, 6 H), 3.12-3.41 (m, 5 H),1.62-2.40 (m, 8 H).

Example 118

4-Bromo-N-[1-(4-dimethylamino-quinazolin-2-yl)-piperidin-4-yl]-2-trifluoromethoxy-benzenesulfonamide

Step A: Synthesis of[2-(4-amino-piperidin-1-yl)-quinazolin-4-yl]-dimethyl-amine.

To a solution of 1-benzyl-piperidin-4-ylamine (2.00 g, 10.5 mmol) in THF(20 mL) was added (Boc)₂O (2.52 g, 11.5 mmol). The mixture was stirredat ambient temperature for 40 min, and concentrated. To a solution ofthe residue in MeOH (20 mL) was added 20% Pd(OH)₂ (400 mg). The mixturewas stirred at ambient temperature under hydrogen atmosphere for 20 hr.Additionally, 20% Pd(OH)₂ (400 mg) was added and the mixture was stirredat ambient temperature under hydrogen atmosphere for 7 hr, at 50° C. for4.5 hr, and at ambient temperature for 12 hr, filtered through a pad ofcelite, and concentrated to give a white solid. A mixture of(2-chloro-quinazolin-4-yl)-dimethyl-amine obtained in step B of example1 (1.10 g, 5.30 mmol) and the above solid (1.27 g, 6.34 mmol) in2-propanol (11 mL) was stirred at reflux for 20 hr. The precipitate wascollected by filtration, washed with 2-propanol, dissolved in 50% MeOHin CHCl₃ (60 mL). The solution was poured into saturated aqueous NaHCO₃,and the aqueous layer was extracted with CHCl₃ (three times). Thecombined organic layer was dried over MgSO₄, filtered, concentrated, andpurified by flash chromatography (NH-silica gel, EtOAc to CHCl₃) to give[2-(4-amino-piperidin-1-yl)-quinazolin-4-yl]-dimethyl-amine (864 mg,68%) as a colorless oil.

ESI MS m/e 272, M+H⁺; ¹H NMR (300 MHz, CDCl₃) δ 7.79 (d, J=8.2 Hz, 1 H),7.45-7.55 (m, 2 H), 6.96-7.05 (m, 1 H), 4.83 (d, J=13.4 Hz, 2 H), 3.26(s, 6 H), 2.84-3.03 (m, 3 H), 1.85-1.95 (m, 2 H), 1.20-1.50 (m, 4 H).

Step B: Synthesis of4-bromo-N-[1-(4-dimethylamino-quinazolin-2-yl)-piperidin-4-yl]-2-trifluoromethoxy-benzenesulfonamide.

Using the procedure for the step A of example 20, the title compound wasobtained.

ESI MS m/e 574, M+H⁺; ¹H NMR (300 MHz, CDCl₃) δ 7.94 (d, J=8.7 Hz, 1 H),7.80 (d, J=8.2 Hz, 1 H), 7.39-7.61 (m, 4 H), 6.98-7.07 (m, 1 H),4.60-4.81 (m, 3 H), 3.39-3.61 (m, 1 H), 3.25 (s, 6 H), 2.98-3.08 (m, 2H), 1.73-1.92 (m, 2 H), 1.33-1.54 (m, 2 H).

Example 119

{2-[4-(4-Bromo-2-trifluoromethoxy-benzylamino)-piperidin-1-yl]-quinazolin-4-yl}-dimethyl-aminedihydrochloride

Step A: Synthesis of{2-[4-(4-bromo-2-trifluoromethoxy-benzylamino)-piperidin-1-yl]-quinazolin-4-yl}-dimethyl-aminedihydrochloride.

Using the procedure for the step B of example 37, the title compound wasobtained.

ESI MS m/e 524, M (free)+H⁺; ¹H NMR (300 MHz, CDCl₃) δ 8.43 (d, J=8.1Hz, 1 H), 8.20 (d, J=8.4 Hz, 1 H), 7.90 (d, J=8.4 Hz, 1 H), 7.67 (t,J=7.5 Hz, 1 H), 7.26-7.49 (m, 3 H), 5.13 (brs, 2 H), 4.27 (s, 2 H),3.08-3.60 (s, 9 H), 2.08-2.78 (m, 4 H).

Example 120

4-Bromo-N-[1-(4-dimethylamino-quinazolin-2-yl)-piperidin-4-yl]-2-trifluoromethoxy-benzamidehydrochloride

Step A: Synthesis of4-bromo-N-[1-(4-dimethylamino-quinazolin-2-yl)-piperidin-4-yl]-2-trifluoromethoxy-benzamidehydrochloride.

Using the procedure for the step A of example 47, the title compound wasobtained.

ESI MS m/e 560, M (free) Na⁺; ¹H NMR (300 MHz, CDCl₃) δ 13.68 (s, 1 H),8.73 (d, J=7.8 Hz, 1 H), 7.80-7.91 (m, 2 H), 7.68 (ddd, J=8.4, 7.1, 1.3Hz, 1 H), 7.55 (dd, J=8.4, 1.9 Hz, 1 H), 7.42-7.46 (m, 1 H), 7.29 (ddd,J=8.4, 7.1, 1.3 Hz, 1 H), 6.67 (d, J=7.3 Hz, 1 H), 5.04 (brs, 2 H),4.23-4.42 (m, 1 H), 3.27-3.61 (m, 8 H), 2.19-2.36 (m, 2 H), 1.57-1.81(m, 2 H).

Example 121

2-(4-Bromo-2-trifluoromethoxy-phenyl)-N-[1-(4-dimethylamino-quinazolin-2-yl)-piperidin-4-yl]-acetamidehydrochloride

Step A: Synthesis of2-(4-bromo-2-trifluoromethoxy-phenyl)-N-[1-(4-dimethylamino-quinazolin-2-yl)-piperidin-4-yl]-acetamidehydrochloride.

Using the procedure for the step A of example 47, the title compound wasobtained.

ESI MS m/e 574, M (free)+Na⁺; ¹H NMR (300 MHz, CDCl₃) δ 13.08 (s, 1 H),8.61 (d, J=8.4 Hz, 1 H), 7.86 (d, J=7.5 Hz, 1 H), 7.56-7.68 (m, 2 H),7.21-7.39 (m, 4 H), 4.70-5.10 (m, 2 H), 4.04-4.22 (m, 1 H), 3.68 (s, 2H), 3.34-3.61 (m, 8 H), 1.59-2.19 (m, 4 H).

Example 122-301

To a solution of amine obtained in step A of example 15 (30 μmol) andpyridine (120 μmol) in CH₂Cl₂ (400 μL) was added an appropriate sulfonylchloride (60 μmol) in CH₂Cl₂ (200 μL) at 25° C. After stirring at thesame temperature for 20 hr, the reaction mixture was concentrated by astream of dry N₂. To the residue was partitionated between CHCl₃ andsaturated aqueous NH₄Cl. The aqueous layer was extracted with CHCl₃. Thecombined organic layers were dried over MgSO₄. After concentration by astream of dry N₂, dry CH₂Cl₂ (600 μL) and PSA (300 μL) were added to theresidue. After the stirring at 25° C. for 20 hr, the reaction mixturewas filtrated and purified by flash chromatography (NH-silica gel, 33%MeOH in CHCl₃) to give the desired product.

Example 302-588

To a solution of amine obtained in step C of example 9 or step A ofexample 64 (30 μmol) in CH₂Cl₂ (200 μL) were added poly(4-vinylpyridine)(75 μL) in CH₂Cl₂ (200 μL) and acid chloride (60 μmol) in CH₂Cl₂ (200μL) at 25° C. After stirring at the same temperature for 20 hr, thereaction mixture was filtered and concentrated by a stream of dry N₂. Tothe residue were added dry CH₂Cl₂ (600 μL) and PSA (300 μL). After thestirring at 25° C. for 20 hr, the reaction mixture was filtrated andpurified by flash chromatography (NH-silica gel, 33% MeOH in CHCl₃) togive the desired product.

Example 589-1136

To a solution of carboxylic acid (200 μL, 60 μmol) in CH₂Cl₂ (200 μL)were added 1-cyclohexyl-3-methylpolystyrene-carbodiimide (150 μL, 126μmol) in CH₂Cl₂ (200 μL) and amine obtained in step C of example 9 orstep A of example 64 (30 μmol) in CH₂Cl₂ (200 μL) at 25° C. Afterstirring at the same temperature for 20 hr, the reaction mixture wasfiltered through NH-silica gel, and concentrated by a stream of dry N₂.To the residue were added dry CH₂Cl₂ (700 μL) and polystyrene linkedbenzaldehyde (75 μL, 60 μmol). After the stirring at 50° C. for 20 hr,the reaction mixture was filtrated, and concentrated by a stream of dryN₂ to give the desired product.

Example 1137-1745

To a solution of the amide product in THF (200 μl) was added 1 Mborane-THF complex in THF (300 μl, 300 μmol). The mixture was stirred at80° C. for 1 hr, and concentrated by a stream of dry N₂. To the residuewere added 1 M aqueous HCl (300 μl) and THF (300 μl). The mixture wasstirred at 80° C. for 1 hr, and concentrated by a stream of dry N₂. Tothe residue was partitionated between CHCl₃ and 2 M aqueous sodiumhydroxide. The aqueous layer was extracted with CHCl₃. The combinedorganic layers were dried over MgSO₄. The mixture was concentrated by astream of dry N₂, and the purified by flash chromatography (silica gel,2% to 7% 2 M NH₃/MeOH in CHCl₃) to give the desired product.

Example 1746-2184

To a solution of amine obtained in step C of example 9 or step A ofexample 64 (36 μmol) in MeOH (200 μL) were added aldehyde (30 μmol) inMeOH (200 μL) and AcOH (90 μmol) at 25° C. The reaction mixture wasstirred at the same temperature for 1 hr. To the mixture was addedNaBH₃CN (120 μmol) in MeOH (200 μL). After stirring at the sametemperature for 20 hr, the reaction mixture was concentrated by a streamof dry N₂. To the residue was partitionated between CHCl₃ and 2 Maqueous sodium hydroxide. The aqueous layer was extracted with CHCl₃.The combined organic layers were dried over MgSO₄. The mixture wasconcentrated by a stream of dry N₂, and purified by flash chromatography(silica gel, 2% to 7% 2 M NH₃/MeOH in CHCl₃) to give the desiredproduct.

Example 2185-2328

To a solution of alcohol (35 μmol) in CH₂Cl₂ (200 μL) was addedDess-Martin periodinane (63 μmol) in CH₂Cl₂ (200 μL) at 25° C., and thereaction mixture was stirred at the same temperature for 20 hr. To thereaction mixture were added amine obtained in step C of example 9 orstep A of example 64 (36 μmol) in MeOH (200 μL) and AcOH (90 μL), andthe mixture was stirred at the same temperature for 1 hr. To the mixturewas added NaBH₃CN (120 μmol) in MeOH (200 μL). After stirring at thesame temperature for 20 hr, the reaction mixture was concentrated by astream of dry N₂. To the residue was partitionated between CHCl₃ and 2 Maqueous sodium hydroxide. The aqueous layer was extracted with CHCl₃.The combined organic layers were dried over MgSO₄. The mixture wasconcentrated by a stream of dry N₂, and purified by flash chromatography(silica gel, 2% to 7% 2 M NH₃/MeOH in CHCl₃) to give the desiredproduct.

Example No. Structure APCI-MS 122

472 (M + H) 123

532 (M + H) 124

511 (M + H) 125

496 (M + H) 126

616 (M + H) 127

532 (M + H) 128

526 (M + H) 129

510 (M + H) 130

538 (M + H) 131

631 (M + H) 132

488 (M + H) 133

650 (M + H) 134

494 (M + H) 135

479 (M + H) 136

479 (M + H) 137

558 (M + H) 138

502 (M + H) 139

516 (M + H) 140

536 (M + H) 141

646 (M + H) 142

601 (M + H) 143

522 (M + H) 144

528 (M + H) 145

514 (M + H) 146

482 (M + H) 147

527 (M + H) 148

496 (M + H) 149

484 (M + H) 150

513 (M + H) 151

529 (M + H) 152

532 (M + H) 153

557 (M + H) 154

532 (M + H) 155

458 (M + H) 156

499 (M + H) 157

499 (M + H) 158

499 (M + H) 159

567 (M + H) 160

490 (M + H) 161

544 (M + H) 162

580 (M + H) 163

558 (M + H) 164

505 (M + H) 165

460 (M + H) 166

556 (M + H) 167

580 (M + H) 168

522 (M + H) 169

468 (M + H) 170

480 (M + H) 171

468 (M + H) 172

595 (M + H) 173

605 (M + H) 174

522 (M + H) 175

482 (M + H) 176

622 (M + H) 177

653 (M + H) 178

544 (M + H) 179

606 (M + H) 180

600 (M + H) 181

600 (M + H) 182

567 (M + H) 183

572 (M + H) 184

572 (M + H) 185

506 (M + H) 186

473 (M + H) 187

472 (M + H) 188

518 (M + H) 189

627 (M + H) 190

548 (M + H) 191

608 (M + H) 192

472 (M + H) 193

514 (M + H) 194

681 (M + H) 195

640 (M + H) 196

715 (M + H) 197

662 (M + H) 198

530 (M + H) 199

502 (M + H) 200

516 (M + H) 201

515 (M + H) 202

486 (M + H) 203

545 (M + H) 204

512 (M + H) 205

530 (M + H) 206

496 (M + H) 207

556 (M + H) 208

510 (M + H) 209

522 (M + H) 210

502 (M + H) 211

498 (M + H) 212

502 (M + H) 213

506 (M + H) 214

484 (M + H) 215

568 (M + H) 216

526 (M + H) 217

524 (M + H) 218

562 (M + H) 219

486 (M + H) 220

524 (M + H) 221

649 (M + H) 222

601 (M + H) 223

490 (M + H) 224

610 (M + H) 225

498 (M + H) 226

522 (M + H) 227

538 (M + H) 228

479 (M + H) 229

546 (M + H) 230

556 (M + H) 231

522 (M + H) 232

506 (M + H) 233

496 (M + H) 234

580 (M + H) 235

520 (M + H) 236

693 (M + H) 237

560 (M + H) 238

546 (M + H) 239

524 (M + H) 240

527 (M + H) 241

513 (M + H) 242

508 (M + H) 243

490 (M + H) 244

590 (M + H) 245

524 (M + H) 246

490 (M + H) 247

550 (M + H) 248

524 (M + H) 249

568 (M + H) 250

524 (M + H) 251

530 (M + H) 252

513 (M + H) 253

530 (M + H) 254

513 (M + H) 255

532 (M + H) 256

480 (M + H) 257

468 (M + H) 258

536 (M + H) 259

536 (M + H) 260

502 (M + H) 261

486 (M + H) 262

482 (M + H) 263

536 (M + H) 264

604 (M + H) 265

536 (M + H) 266

592 (M + H) 267

626 (M + H) 268

558 (M + H) 269

434 (M + H) 270

518 (M + H) 271

454 (M + H) 272

556 (M + H) 273

528 (M + H) 274

528 (M + H) 275

406 (M + H) 276

602 (M + H) 277

420 (M + H) 278

392 (M + H) 279

490 (M + H) 280

420 (M + H) 281

446 (M + H) 282

538 (M + H) 283

460 (M + H) 284

454 (M + H) 285

532 (M + H) 286

510 (M + H) 287

532 (M + H) 288

616 (M + H) 289

488 (M + H) 290

522 (M + H) 291

528 (M + H) 292

547 (M + H) 293

472 (M + H) 294

504 (M + H) 295

504 (M + H) 296

468 (M + H) 297

538 (M + H) 298

522 (M + H) 299

488 (M + H) 300

590 (M + H) 301

522 (M + H) 302

520 (M + H) 303

390 (M + H) 304

446 (M + H) 305

468 (M + H) 306

468 (M + H) 307

432 (M + H) 308

505 (M + H) 309

536 (M + H) 310

469 (M + H) 311

504 (M + H) 312

430 (M + H) 313

433 (M + H) 314

408 (M + H) 315

451 (M + H) 316

380 (M + H) 317

476 (M + H) 318

391 (M + H) 319

437 (M + H) 320

448 (M + H) 321

471 (M + H) 322

470 (M + H) 323

412 (M + H) 324

557 (M + H) 325

391 (M + H) 326

435 (M + H) 327

425 (M + H) 328

569 (M + H) 329

391 (M + H) 330

524 (M + H) 331

498 (M + H) 332

442 (M + H) 333

396 (M + H) 334

516 (M + H) 335

474 (M + H) 336

474 (M + H) 337

444 (M + H) 338

482 (M + H) 339

516 (M + H) 340

458 (M + H) 341

498 (M + H) 342

442 (M + H) 343

440 (M + H) 344

442 (M + H) 345

442 (M + H) 346

460 (M + H) 347

476 (M + H) 348

476 (M + H) 349

462 (M + H) 350

516 (M + H) 351

480 (M + H) 352

432 (M + H) 353

408 (M + H) 354

442 (M + H) 355

434 (M + H) 356

442 (M + H) 357

422 (M + H) 358

406 (M + H) 359

490 (M + H) 360

440 (M + H) 361

510 (M + H) 362

456 (M + H) 363

456 (M + H) 364

422 (M + H) 365

460 (M + H) 366

472 (M + H) 367

498 (M + H) 368

464 (M + H) 369

418 (M + H) 370

539 (M + H) 371

465 (M + H) 372

499 (M + H) 373

497 (M + H) 374

558 (M + H) 375

526 (M + H) 376

450 (M + H) 377

395 (M + H) 378

553 (M + H) 379

500 (M + H) 380

469 (M + H) 381

532 (M + H) 382

450 (M + H) 383

529 (M + H) 384

515 (M + H) 385

594 (M + H) 386

553 (M + H) 387

473 (M + H) 388

428 (M + H) 389

450 (M + H) 390

502 (M + H) 391

508 (M + H) 392

472 (M + H) 393

476 (M + H) 394

479 (M + H) 395

446 (M + H) 396

462 (M + H) 397

510 (M + H) 398

454 (M + H) 399

416 (M + H) 400

438 (M + H) 401

492 (M + H) 402

457 (M + H) 403

420 (M + H) 404

404 (M + H) 405

430 (M + H) 406

448 (M + H) 407

465 (M + H) 408

434 (M + H) 409

410 (M + H) 410

587 (M + H) 411

420 (M + H) 412

465 (M + H) 413

525 (M + H) 414

448 (M + H) 415

510 (M + H) 416

464 (M + H) 417

432 (M + H) 418

422 (M + H) 419

434 (M + H) 420

476 (M + H) 421

418 (M + H) 422

623 (M + H) 423

618 (M + H) 424

484 (M + H) 425

461 (M + H) 426

482 (M + H) 427

450 (M + H) 428

454 (M + H) 429

430 (M + H) 430

482 (M + H) 431

454 (M + H) 432

500 (M + H) 433

478 (M + H) 434

543 (M + H) 435

502 (M + H) 436

473 (M + H) 437

489 (M + H) 438

328 (M + H) 439

328 (M + H) 440

396 (M + H) 441

384 (M + H) 442

356 (M + H) 443

399 (M + H) 444

396 (M + H) 445

384 (M + H) 446

439 (M + H) 447

534 (M + H) 448

404 (M + H) 449

460 (M + H) 450

482 (M + H) 451

482 (M + H) 452

446 (M + H) 453

519 (M + H) 454

550 (M + H) 455

483 (M + H) 456

518 (M + H) 457

444 (M + H) 458

447 (M + H) 459

422 (M + H) 460

465 (M + H) 461

394 (M + H) 462

490 (M + H) 463

405 (M + H) 464

451 (M + H) 465

462 (M + H) 466

485 (M + H) 467

484 (M + H) 468

426 (M + H) 469

571 (M + H) 470

405 (M + H) 471

449 (M + H) 472

439 (M + H) 473

583 (M + H) 474

405 (M + H) 475

538 (M + H) 476

512 (M + H) 477

456 (M + H) 478

410 (M + H) 479

530 (M + H) 480

488 (M + H) 481

488 (M + H) 482

458 (M + H) 483

496 (M + H) 484

530 (M + H) 485

472 (M + H) 486

512 (M + H) 487

456 (M + H) 488

454 (M + H) 489

456 (M + H) 490

456 (M + H) 491

474 (M + H) 492

490 (M + H) 493

490 (M + H) 494

476 (M + H) 495

530 (M + H) 496

494 (M + H) 497

446 (M + H) 498

422 (M + H) 499

488 (M + H) 500

448 (M + H) 501

456 (M + H) 502

436 (M + H) 503

420 (M + H) 504

504 (M + H) 505

454 (M + H) 506

524 (M + H) 507

470 (M + H) 508

470 (M + H) 509

436 (M + H) 510

474 (M + H) 511

486 (M + H) 512

512 (M + H) 513

478 (M + H) 514

432 (M + H) 515

553 (M + H) 516

479 (M + H) 517

513 (M + H) 518

511 (M + H) 519

572 (M + H) 520

540 (M + H) 521

464 (M + H) 522

409 (M + H) 523

567 (M + H) 524

514 (M + H) 525

483 (M + H) 526

546 (M + H) 527

464 (M + H) 528

543 (M + H) 529

529 (M + H) 530

608 (M + H) 531

567 (M + H) 532

487 (M + H) 533

442 (M + H) 534

464 (M + H) 535

516 (M + H) 536

522 (M + H) 537

486 (M + H) 538

490 (M + H) 539

493 (M + H) 540

460 (M + H) 541

476 (M + H) 542

524 (M + H) 543

468 (M + H) 544

430 (M + H) 545

452 (M + H) 546

506 (M + H) 547

471 (M + H) 548

434 (M + H) 549

418 (M + H) 550

444 (M + H) 551

462 (M + H) 552

479 (M + H) 553

448 (M + H) 554

424 (M + H) 555

601 (M + H) 556

462 (M + H) 557

524 (M + H) 558

478 (M + H) 559

446 (M + H) 560

436 (M + H) 561

448 (M + H) 562

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623 (M + H) 1354

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440 (M + H) 2218

446 (M + H) 2219

434 (M + H) 2220

446 (M + H) 2221

404 (M + H) 2222

408 (M + H) 2223

420 (M + H) 2224

420 (M + H) 2225

463 (M + H) 2226

460 (M + H) 2227

462 (M + H) 2228

502 (M + H) 2229

434 (M + H) 2230

456 (M + H) 2231

432 (M + H) 2232

460 (M + H) 2233

488 (M + H) 2234

474 (M + H) 2235

446 (M + H) 2236

484 (M + H) 2237

420 (M + H) 2238

568 (M + H) 2239

428 (M + H) 2240

396 (M + H) 2241

420 (M + H) 2242

468 (M + H) 2243

432 (M + H) 2244

468 (M + H) 2245

458 (M + H) 2246

423 (M + H) 2247

420 (M + H) 2248

404 (M + H) 2249

448 (M + H) 2250

446 (M + H) 2251

540 (M + H) 2252

470 (M + H) 2253

472 (M + H) 2254

479 (M + H) 2255

433 (M + H) 2256

458 (M + H) 2257

515 (M + H) 2258

410 (M + H) 2259

394 (M + H) 2260

368 (M + H) 2261

372 (M + H) 2262

397 (M + H) 2263

464 (M + H) 2264

462 (M + H) 2265

458 (M + H) 2266

492 (M + H) 2267

448 (M + H) 2268

460 (M + H) 2269

434 (M + H) 2270

454 (M + H) 2271

478 (M + H) 2272

462 (M + H) 2273

516 (M + H) 2274

476 (M + H) 2275

522 (M + H) 2276

454 (M + H) 2277

502 (M + H) 2278

530 (M + H) 2279

418 (M + H) 2280

492 (M + H) 2281

470 (M + H) 2282

478 (M + H) 2283

470 (M + H) 2284

464 (M + H) 2285

456 (M + H) 2286

422 (M + H) 2287

438 (M + H) 2288

462 (M + H) 2289

472 (M + H) 2290

472 (M + H) 2291

434 (M + H) 2292

433 (M + H) 2293

454 (M + H) 2294

460 (M + H) 2295

448 (M + H) 2296

460 (M + H) 2297

422 (M + H) 2298

474 (M + H) 2299

476 (M + H) 2300

516 (M + H) 2301

448 (M + H) 2302

470 (M + H) 2303

446 (M + H) 2304

488 (M + H) 2305

460 (M + H) 2306

434 (M + H) 2307

582 (M + H) 2308

442 (M + H) 2309

419 (M + H) 2310

434 (M + H) 2311

482 (M + H) 2312

418 (M + H) 2313

446 (M + H) 2314

482 (M + H) 2315

472 (M + H) 2316

437 (M + H) 2317

434 (M + H) 2318

418 (M + H) 2319

462 (M + H) 2320

460 (M + H) 2321

554 (M + H) 2322

470 (M + H) 2323

537 (M + H) 2324

529 (M + H) 2325

424 (M + H) 2326

408 (M + H) 2327

382 (M + H) 2328

386 (M + H)

Example 2329

trans-4-Bromo-N-{4-[(4-methylamino-quinazolin-2-ylamino)-methyl]-cyclohexylmethyl}-2-trifluoromethoxy-benzenesulfonamidehydrochloride

Step A: Synthesis oftrans-4-[(4-bromo-2-trifluoromethoxy-benzenesulfonylamino)-methyl]-cyclohexanecarboxylicacid.

To a solution of trans-4-aminomethyl-cyclohexanecarboxylic acid (3.14 g,20 mmol) in THF (20 mL) and 1 M aqueous sodium hydroxide (42 mL) wasadded a solution of 4-bromo-2-trifluoromethoxy benzenesulfonyl chloride(6.9 g, 20.4 mmol) in THF (20 mL) and the mixture was stirred for 2 hrat ambient temperature. The resulting mixture was concentrated and 1 Maqueous HCl (45 mL) was added. The resulting precipitate was filtered,washed with water and hexanes to givetrans-4-[(4-bromo-2-trifluoromethoxy-benzenesulfonylamino)-methyl]-cyclohexanecarboxylicacid (7.18 g, 78%) as a white powder.

ESI MS m/e 460/462 M+H⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 12.00 (brs, 1 H),7.99 (brs, 1 H), 7.84-7.80 (m, 3 H), 2.72 (d, J=6.3 Hz, 2 H), 2.10 (m, 1H), 1.86 (m, 2 H), 1.71 (m, 2 H), 1.31 (m, 1 H), 1.23 (m, 2 H), 0.87 (m,2 H).

Step B: Synthesis oftrans-4-[(4-bromo-2-trifluoromethoxy-benzenesulfonylamino)-methyl]-cyclohexanecarboxylicacid amide.

A solution oftrans-4-[(4-bromo-2-trifluoromethoxy-benzenesulfonylamino)-methyl]-cyclohexanecarboxylicacid (7.14 g, 15.5 mmol) and triethylamine (2.35 mL, 16.9 mmol) in THF(25 mL) was cooled to 0° C. To the mixture was added ethyl chloroformate(1.62 mL, 17 mmol) in THF (5 mL) over 10 min. After stirring at 0° C.for 15 min, aqueous ammonia (27 mL) was added dropwise and the mixturewas stirred at ambient temperature for 2 hr. The mixture wasconcentrated under reduced pressure and the concentrate was treated withwater to give a solid. The solid was filtered and washed with water andhexanes to givetrans-4-[(4-bromo-2-trifluoromethoxy-benzenesulfonylamino)-methyl]-cyclohexanecarboxylicacid amide as a white solid (4.2 g, 59%).

ESI MS m/e 459/461 M+H⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 7.98 (brs, 1 H),7.84-7.80 (m, 3 H), 7.13 (s, 1 H), 6.62 (s, 1 H), 2.72 (d, J=6.5 Hz, 2H), 1.98 (m, 1 H), 1.70 (m, 4 H), 1.29 (m, 1 H), 1.23 (m, 2 H), 0.83 (m,2 H).

Step C: Synthesis oftrans-N-(4-aminomethyl-cyclohexylmethyl)-4-bromo-2-trifluoromethoxy-benzenesulfonamide.

To a solution oftrans-4-[(4-bromo-2-trifluoromethoxy-benzenesulfonylamino)-methyl]-cyclohexanecarboxylicacid amide (4.2 g, 9.2 mmol) in THF (40 mL) was added a solution of 1 MBH₃ in THF (32 mL, 32 mmol) over 40 min. The mixture was refluxed for 2hr. After cooling to 0° C., the mixture was quenched with water (7 mL).To the resulting mixture were added 4 M HCl in EtOAc (28 mL) and MeOH(28 mL) and the mixture was concentrated. To the residue was added MeOH(28 mL) and the mixture was once again concentrated. The resultingHCl-salt was recrystallized from Et₂O and subsequently neutralized with1 M aqueous sodium hydroxide. The aqueous layer was extracted withCH₂Cl₂ (twice), the organic layers combined, dried over sodium sulfate,and concentrated under reduced pressure to givetrans-N-(4-aminomethyl-cyclohexylmethyl)-4-bromo-2-trifluoromethoxy-benzenesulfonamideas a white solid (3.0 g, 74%).

ESI MS m/e 445/447 M+H⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 7.84-7.79 (m, 3 H),3.42 (brs, 2 H), 2.72 (d, J=6.8 Hz, 2 H), 2.33 (d, J=6.5 Hz, 2 H), 1.73(m, 4 H), 1.27 (m, 1 H), 1.09 (m, 1 H), 0.80 (m, 4 H).

Step D: Synthesis oftrans-4-Bromo-N-{4-[(4-methylamino-quinazolin-2-ylamino)-methyl]-cyclohexylmethyl}-2-trifluoromethoxy-benzenesulfonamidehydrochloride.

A mixture of (2-chloro-quinazolin-4-yl)-methylamine obtained in step Aof example 50 (58 mg, 0.3 mmol) andtrans-N-(4-aminomethyl-cyclohexylmethyl)-4-bromo-2-trifluoromethoxy-benzenesulfonamideamide (133 mg, 0.3 mmol) in 2-propanol (0.5 mL) was stirred at refluxfor 24 hr. The mixture was cooled and the resulting white solid wascollected by filtration and washed with 2-propanol to givetrans-4-Bromo-N-{4-[(4-methylamino-quinazolin-2-ylamino)-methyl]-cyclohexylmethyl}-2-trifluoromethoxy-benzenesulfonamidehydrochloride as a white solid (121 mg, 67%).

ESI MS m/e 602/604 M+H⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 12.61 (brs, 1 H),9.70 (brs, 1 H), 8.26 (d, J=8.1 Hz, 1 H), 8.15 (brs, 1 H), 8.02 (t,J=5.7 Hz, 1 H), 7.84-7.74 (m, 4 H), 7.41 (m, 1 H), 3.32 (m, 2 H), 3.07(d, J=3.5 Hz, 3 H), 2.73 (t, J=6.2 Hz, 2 H), 1.77 (m, 4 H), 1.53 (m, 1H), 1.32 (m, 1 H), 0.96 (m, 2 H), 0.82 (m, 2 H).

Example 2330

trans-N-{4-[(4-Dimethylamino-quinazolin-2-ylamino)-methyl]-cyclohexylmethyl}-2,5-bis-(2,2,2-trifluoro-ethoxy)-benzenesulfonamidehydrochloride

Step A: Synthesis oftrans-4-{[2,5-bis-(2,2,2-trifluoro-ethoxy)-benzenesulfonylamino]-methyl}-cyclohexanecarboxylicacid.

To a solution of trans-4-aminomethyl-cyclohexanecarboxylic acid (1.5 g,10 mmol) in THF (10 mL) and 1 M aqueous sodium hydroxide (27 mL) wasadded a solution of 2,5-bis(2,2,2-trifluoroethoxy)benzenesulfonylchloride (3.8 g, 10.25 mmol) in THF (10 mL) dropwise and the mixture wasstirred at ambient temperature for 2 hr. The resulting mixture wasconcentrated and 1 M aqueous HCl (22.5 mL) was added. The resultingprecipitate was filtered, washed with water and hexanes to givetrans-4-{[2,5-bis-(2,2,2-trifluoro-ethoxy)-benzenesulfonylamino]-methyl}-cyclohexanecarboxylicacid as a white powder (2.8 g, 57%).

ESI MS m/e 494 M+H⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 7.36 (m, 3 H), 7.23(brs, 1 H), 4.88 (m, 4 H), 2.73 (m, 2 H), 2.10 (m, 1 H), 1.87 (m, 2 H),1.72 (m, 2 H), 1.30 (m, 1 H), 1.23 (m, 2 H), 0.87 (m, 2 H).

Step B: Synthesis oftrans-4-{[2,5-bis-(2,2,2-trifluoro-ethoxy)-benzenesulfonylamino]-methyl}-cyclohexanecarboxylicacid amide.

A solution oftrans-4-{[2,5-bis-(2,2,2-trifluoro-ethoxy)-benzenesulfonylamino]-methyl}-cyclohexanecarboxylicacid (2.78 g, 5.63 mmol) and triethylamine (1.9 mL, 13.6 mmol) in THF(25 mL) was cooled to 0° C. To the mixture was added ethyl chloroformate(0.586 mL, 6.2 mmol) in THF (5 mL) over 10 min. After stirring at 0° C.for 15 min, 25% aqueous ammonia (10 mL) was added dropwise. The mixturewas stirred at ambient temperature for 2 hr. The resulting mixture wasconcentrated under reduced pressure and the concentrate was diluted withwater to give a solid. The solid was filtered and washed with water andhexanes to givetrans-4-{[2,5-bis-(2,2,2-trifluoro-ethoxy)-benzenesulfonylamino]-methyl}-cyclohexanecarboxylicacid amide as a white solid (2.7 g, 98%).

ESI MS m/e 493 M+H⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 7.36 (m, 3 H), 7.23 (t,J=6.1 Hz, 1 H), 7.13 (s, 1 H), 6.62 (s, 1 H), 4.88 (m, 4 H), 2.74 (t,J=6.4 Hz, 2 H), 1.99 (m, 1 H), 1.75 (m, 4 H), 1.28 (m, 1 H), 1.23 (m, 2H), 0.83 (m, 2 H).

Step C: Synthesis oftrans-N-(4-aminomethyl-cyclohexylmethyl)-2,5-bis-(2,2,2-trifluoro-ethoxy)-benzenesulfonamide.

To a solution oftrans-4-{[2,5-bis-(2,2,2-trifluoro-ethoxy)-benzenesulfonylamino]-methyl}-cyclohexanecarboxylicacid amide (2.7 g, 5.5 mmol) in THF (20 mL) was added a solution of 1 MBH₃ in THF (20 mL, 20 mmol) over 40 min. The mixture was stirred atreflux for 2 hr. After cooling to 0° C., the mixture was quenched withwater (7 mL). To the mixture were added 4 M HCl in EtOAc (28 mL) andMeOH (50 mL) and the mixture was concentrated. To the residue was addedMeOH (50 mL) and the mixture was once again concentrated. The resultingHCl-salt was recrystallized from Et₂O and subsequently neutralized with1 M aqueous sodium hydroxide. The aqueous layer was extracted withCH₂Cl₂ (twice), the combined organic layers were dried over sodiumsulfate, and concentrated under reduced pressure to givetrans-N-(4-aminomethyl-cyclohexylmethyl)-2,5-bis-(2,2,2-trifluoro-ethoxy)-benzenesulfonamideas a white solid (1.5 g, 57%).

ESI MS m/e 479 M+H⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 7.36-7.32 (m, 3 H),6.62 (brs, 1 H), 4.88-4.78 (m, 4 H), 3.42 (b, 2 H), 2.73 (d, J=6.6 Hz, 2H), 2.34 (d, J=6.3 Hz, 2 H), 1.73 (m, 4 H), 1.27 (m, 1 H), 1.10 (m, 1H), 0.77 (m, 4 H).

Step D: Synthesis oftrans-N-{4-[(4-Dimethylamino-quinazolin-2-ylamino)-methyl]-cyclohexylmethyl}-2,5-bis-(2,2,2-trifluoro-ethoxy)-benzenesulfonamidehydrochloride.

A mixture of (2-chloro-quinazoline-4-yl)-dimethyl-amine obtained in stepB of example 1 (41.4 mg, 0.2 mmol) andtrans-AT-(4-aminomethyl-cyclohexylmethyl)-2,5-bis-(2,2,2-trifluoro-ethoxy)-benzenesulfonamide(95.6 mg, 0.2 mmol) in 2-propanol was stirred at reflux for 24 hr. Thereaction mixture was concentrated and the residue was purified by columnchromatography (silica gel) to give the product as a white foam. Theproduct was dissolved in CH₂Cl₂ and treated with 1 M HCl in Et₂O. Themixture was concentrated to givetrans-N-{4-[(4-Dimethylamino-quinazolin-2-ylamino)-methyl]-cyclohexylmethyl}-2,5-bis-(2,2,2-trifluoro-ethoxy)-benzenesulfonamidehydrochloride as a white foam (101 mg, 78%).

ESI MS m/e 650 M+H⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 8.16 (d, J=8.2 Hz, 1H), 8.00 (brs, 1 H), 7.78 (t, J=7.9, 1 H), 7.44 (brs, 1 H), 7.34 (m,4H), 7.24 (t, J=5.9 Hz, 1 H), 4.88 (m, 4 H), 3.32 (s, 6 H), 3.29 (m, 2H), 2.75 (t, J=6.2 Hz, 2 H), 1.74 (m, 4 H), 1.52 (m, 1 H), 1.32 (m, 1H), 0.94 (m, 2 H), 0.83 (m, 2 H).

Example 2331

trans-4-Bromo-N-(4-guanidinomethyl-cyclohexylmethyl)-2-trifluoromethoxy-benzenesulfonamidedihydrochloride

Step A: Synthesis oftrans-[({4-[(4-bromo-2-trifluoromethoxy-benzenesulfonylamino)-methyl]-cyclohexylmethyl}-amino)-tert-butoxycarbonylamino-methyl]-carbamicacid tert-butyl ester.

To a solution oftrans-N-(4-aminomethyl-cyclohexylmethyl)-4-bromo-2-trifluoromethoxy-benzenesulfonamideobtain in step C of example 2329 (45 mg, 0.1 mmol) and triethylamine (14μL, 0.1 mmol) in CH₂Cl₂ (5 mL) was added(tert-butoxycarbonylamino-trifluoromethanesulfonylimino-methyl)-carbamicacid tert-butyl ester (39.1 mg, 0.1 mmol). The reaction mixture wasstirred at ambient temperature for 2 hr and concentrated. The residuewas purified by column chromatography (silica gel, CH₂Cl₂ to 10% MeOH inCH₂Cl₂) to givetrans-[({4-[(4-bromo-2-trifluoromethoxy-benzenesulfonylamino)-methyl]-cyclohexylmethyl}-amino)-tert-butoxycarbonylamino-methyl]-carbamicacid tert-butyl ester as a white solid (63 mg, 92%).

ESI MS m/e 687/689 M+H⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 11.45 (s, 1 H),8.22 (t, J=5.6 Hz, 1 H), 7.97 (t, J=5.6 Hz, 1 H), 7.99-7.79 (m, 3 H),3.13 (t, J=6.4 Hz, 2 H), 2.72 (t, J=6 Hz, 2 H), 1.70 (m, 4 H), 1.46 (s,9 H), 1.38 (s, 9 H), 1.31 (m, 2 H), 0.83 (m, 4 H).

Step B: Synthesis oftrans-4-bromo-N-(4-guanidinomethyl-cyclohexylmethyl)-2-trifluoromethoxy-benzenesulfonamidedihydrochloride.

A solution oftrans-[({4-[(4-bromo-2-trifluoromethoxy-benzenesulfonylamino)-methyl]-cyclohexylmethyl}-amino)-tert-butoxycarbonylamino-methyl]-carbamicacid tert-butyl ester (53 mg, 0.077 mmol) in 50% TFA in CH₂Cl₂ (2 mL)was stirred at ambient temperature for 3 hr and the reaction mixture wasconcentrated. To the residue was added a solution of 1 M HCl in Et₂O(0.5 mL) and the mixture was concentrated to givetrans-4-Bromo-N-(4-guanidinomethyl-cyclohexylmethyl)-2-trifluoromethoxy-benzenesulfonamidedihydrochloride as a white solid (29 mg, 68%).

ESI MS m/e 487/489 M+H⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 8.01 (t, J=5.5 Hz,1 H), 7.84 (m, 3 H), 7.68 (m, 1 H), 7.30 (m, 2 H), 6.85 (m, 2 H), 2.94(t, J=6.1 Hz, 2 H), 2.74 (t, J=6.1 Hz, 2 H), 1.71 (m, 2 H), 1.31 (m, 4H), 0.86 (m, 4 H).

Example 2332

cis-N⁴,N⁴-Dimethyl-N²-{4-[(2-trifluoromethyl-benzylamino)-methyl]-cyclohexyl}-quinazoline-2,4-diamineditrifluoro-acetic acid

Step A: Synthesis ofcis-4-tert-butoxycarbonylamino-cyclohexanecarboxylic acid.

To a solution of cis-4-amino-cyclohexanecarboxylic acid (50 g, 350 mmol)in THF (200 mL) and 1 M aqueous sodium hydroxide (380 mL, 380 mmol) wasadded (Boc)₂O (83.5 g, 360 mmol). The reaction mixture was stirred atambient temperature for 2 hr and concentrated. The residue was cooled to0° C. followed by acidification with 1 M HCl (pH=3). The resulting whitesolid was filtered, washed with water and hexanes to givecis-4-tert-butoxycarbonylamino-cyclohexanecarboxylic acid (71 g, 83%) asa white solid.

ESI MS m/e 244 M+H⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 12.00 (brs, 1 H), 6.74(d, J=4.25, 1 H), 3.30 (brs, 1 H), 2.35 (m, 1 H), 1.87 (m, 2 H),1.55-1.37 (m, 15 H).

Step B: Synthesis of cis-(4-carbamoyl-cyclohexyl)-carbamic acidtert-butyl ester.

To a solution cooled at 0° C. ofcis-4-tert-butoxycarbonylamino-cyclohexanecarboxylic acid (68.0 g, 280mmol) and triethylamine (31.1 g, 307 mmol) in THF (300 mL) was addedethyl chloroformate (29.3 mL, 308 mmol) dropwise. After stirring at 0°C. for 30 min, 25% aqueous ammonia (168 mL) was added dropwise. Thereaction mixture was stirred at ambient temperature for 2 hr andconcentrated. The residue was extracted with EtOAc (three times). Thecombined organic layer was washed with saturated aqueous NaHCO₃, 1 MHCl, brine, and water, dried over Na₂SO₄, filtered, and concentrated togive cis-(4-carbamoyl-cyclohexyl)-carbamic acid tert-butyl ester (62.0g, 88%) as a white solid.

ESI MS m/e 243 M+H⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 7.10 (brs, 1 H), 6.69(b, 2 H), 3.41 (brs, 1 H), 2.14 (m, 1 H), 1.79 (m, 2 H), 1.59 (m, 2 H),1.45-1.37 (m, 13 H).

Step C: Synthesis of cis-4-amino-cyclohexanecarboxylic acid amidehydrochloride.

To a solution of cis-(4-carbamoyl-cyclohexyl)-carbamic acid tert-butylester (62 g, 256 mmol) in CH₂Cl₂ (250 mL) was added TFA (250 mL) and themixture was stirred at ambient temperature for 1 hr. The mixture wasconcentrated and 2 M HCl in Et₂O (150 mL) was added to give a whiteprecipitate. The mixture was concentrated to givecis-4-amino-cyclohexanecarboxylic acid amide hydrochloride (45 g, 98%)as a white solid.

ESI MS m/e 143 M+H⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 8.08 (m, 3 H), 7.28 (s,1 H), 6.78 (s, 1 H), 3.10 (m, 1 H), 2.24 (m, 1 H), 1.90 (m, 2 H), 1.66(m, 4 H), 1.50 (m, 2 H).

Step D: Synthesis ofcis-4-(4-dimethylamino-quinazolin-2-ylamino)-cyclohexanecarboxylic acidamide.

A solution of (2-chloro-quinazolin-4-yl)-dimethyl-amine obtained in stepB of example 1 (31.05 g, 150 mmol) and cis-4-amino-cyclohexanecarboxylicacid amide hydrochloride (26.7 g, 150 mmol) in pyridine (150 mL) wasstirred at reflux for overnight. The reaction mixture was concentratedand residue was dissolve in CH₂Cl₂. The organic layer was washed withsaturated aqueous NaHCO₃ and the aqueous layer was extracted withCH₂Cl₂. The organic layer was dried over Na₂SO₄, filtered andconcentrated. The residue was purified by column chromatography (silicagel, 2% to 10% 2 M NH₃/MeOH in CH₂Cl₂) to give a slightly brown solidand the solid was recrystallized from CH₂Cl₂ to givecis-4-(4-dimethylamino-quinazolin-2-ylamino)-cyclohexanecarboxylic acidamide (20.6 g, 44%) as yellow crystals.

ESI MS m/e 314 M+H⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 8.19 (brs, 1 H), 8.15(d, J=8.4 Hz, 1 H), 7.77 (t, J=8.0 Hz, 1 H), 7.42 (d, J=7.2 Hz, 1 H),7.35 (t, J=8.4 Hz, 1 H), 7.21 (s, 1 H), 6.74 (s, 1 H), 4.12 (m, 1 H),3.46 (m, 6 H), 2.24 (m, 1 H), 1.79-1.61 (m, 8 H).

Step E: Synthesis ofcis-N²-(4-aminomethyl-cyclohexyl)-N⁴,N⁴-dimethyl-quinazoline-2,4-diamine.

To a solution ofcis-4-(4-dimethylamino-quinazolin-2-ylamino)-cyclohexanecarboxylic acidamide (18.78 g, 60 mmol) in THF (200 mL) was added a solution of 1 M BH₃in THF (300 mL, 300 mmol). The mixture was stirred at reflux for 2 hr.After cooling the reaction mixture to 0° C., 4 M HCl in EtOAc (100 mL)and MeOH (200 mL) were added. The mixture was concentrated. The mixturewas treated with 1 M aqueous sodium hydroxide and the aqueous layer wasextracted with CH₂Cl₂. The organic layer was dried over sodium sulfate,concentrated, and purified by column chromatography (silica gel, 10% 2 MNH₃/MeOH in CH₂Cl₂) to givecis-N²-(4-aminomethyl-cyclohexyl)-N⁴,N⁴-dimethyl-quinazoline-2,4-diamineas a white solid (10.6 g, 59%).

ESI MS m/e 300 M+H⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 7.84 (d, J=8.4 Hz, 1H), 7.46 (t, J=6.8 Hz, 1 H), 7.26 (d, J=8.4 Hz, 1 H), 6.99 (t, J=6.8 Hz,1 H), 6.28 (brs, 1 H), 4.02 (m, 1 H), 3.19 (m, 6 H), 2.47 (d, J=6.8 Hz,2 H), 2.73 (m 2 H), 1.68-1.33 (m, 9 H).

Step F: Synthesis ofcis-N⁴,N⁴-dimethyl-N²-{4-[(2-trifluoromethyl-benzylamino)-methyl]-cyclohexyl}-quinazoline-2,4-diamineditrifluoro-acetic acid.

A solution ofcis-N²-(4-aminomethyl-cyclohexyl)-N⁴,N⁴-dimethyl-quinazoline-2,4-diamine(33 mg, 0.11 mmol) and 2-trifluoromethyl benzaldehyde (17.41 mg, 0.11mmol) in MeOH (1 mL) was stirred at ambient temperature for 3 hr. To themixture was added NaBH(OAc)₃ (85 mg, 0.4 mmol) and the mixture wasstirred at ambient temperature for overnight. This resulting mixture wasquenched with 50% DMSO in water (2 mL) and the solution was purified bypreparative HPLC. The pure fractions were combined and lyophilized togivecis-N⁴,N⁴-dimethyl-N²-{4-[(2-trifluoromethyl-benzylamino)-methyl]-cyclohexyl}-quinazoline-2,4-diamineditrifluoro-acetic acid (41.4 mg, 60%) as a white solid.

ESI MS m/e 458 M+H⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 13.12 (brs, 1 H), 8.94(b, 2 H), 8.65 (d, J=6.8 Hz, 1 H), 8.16 (d, J=8.8 Hz, 1 H), 7.77-7.66(m, 5 H), 7.41 (d, J=8.4 Hz, 1 H), 7.35 (t, J=8 Hz, 1 H), 4.22 (s, 2 H),4.17 (m, 1 H), 3.46 (b, 6 H), 2.94 (m, 2 H), 1.87-1.44 (m, 9 H).

Example 2333

cis-5-(4-Chloro-phenyl)-2-trifluoromethyl-furan-3-carboxylic acid[4-(4-dimethylamino-quinazolin-2-ylamino)-cyclohexylmethyl]-amidetrifluoro-acetic acid

Step A: Synthesis ofcis-5-(4-chloro-phenyl)-2-trifluoromethyl-furan-3-carboxylic acid[4-(4-dimethylamino-quinazolin-2-ylamino)-cyclohexylmethyl]-amidetrifluoro-acetic acid.

A solution ofcis-N²-(4-aminomethyl-cyclohexyl)-N⁴,N⁴-dimethyl-quinazoline-2,4-diamineobtained in step E of example 2332 (30 mg, 0.1 mmol),5-(4-chloro-phenyl)-2-trifluoromethyl-furan-3-acid chloride (37 mg, 0.12mmol), and pyridine (12 μL, 0.15 mmol) in DMF (0.5 mL) was stirred atambient temperature for overnight. The resulting mixture was dilutedwith DMSO (0.8 mL) and the mixture was purified by preparative HPLC. Thepure fractions were combined and lyophilized to givecis-5-(4-chloro-phenyl)-2-trifluoromethyl-furan-3-carboxylic acid[4-(4-dimethylamino-quinazolin-2-ylamino)-cyclohexylmethyl]-amidetrifluoro-acetic acid (17.5 mg, 26%) as a white solid.

ESI MS m/e 572 M+H⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 12.30 (brs, 1 H), 8.65(t, J=6.8 Hz, 1 H), 8.19 (brs, 1 H), 8.14 (d, J=8.0 Hz, 1 H), 7.83-7.30(m, 8 H), 4.1 (m, 1 H), 3.46 (b, 6 H), 3.09 (m, 2 H), 1.77-1.38 (m, 9H).

Example 2334

cis-N-[4-(4-Dimethylamino-quinazolin-2-ylamino)-cyclohexylmethyl]-3,4,5-trimethoxy-benzamidetrifluoro-acetic acid

Step A: Synthesis ofcis-N-[4-(4-dimethylamino-quinazolin-2-ylamino)-cyclohexylmethyl]-3,4,5-trimethoxy-benzamidetrifluoro-acetic acid.

To HOBt-6-carboxaamidomethyl polystyrene 200-400 mesh (77 mg, 0.1 mmol)were added a solution of 0.3 M PyBroP in DMF (1 mL, 0.3 mmol),3,4,5-trimethoxybenzoic acid (63 mg, 0.3 mmol), anddiisopropylethylamine (85 μL, 0.5 mmol). The mixture was stirred atambient temperature for 5 hr. The resin was washed with DMF (3 times),CH₂Cl₂ (3 times), MeOH (3 times), CH₂Cl₂ (2 times), and DMF (2 times).To the resin was addedcis-N²-(4-aminomethyl-cyclohexyl)-N⁴,N⁴-dimethyl-quinazoline-2,4-diamineobtained in step E of example 2332 (28 mg, 0.09 mmol) in DMF (0.5 mL)and the mixture was stirred at ambient temperature for overnight. Theresin was filtered and washed with 0.5 mL DMSO (2 times). The combinedfiltrates were purified by preparative HPLC. The pure fractions werecombined and lyophilized to give cisN-[4-(4-dimethylamino-quinazolin-2-ylamino)-cyclohexylmethyl]-3,4,5-trimethoxy-benzamidetrifluoro-acetic acid (7.4 mg, 12%) as a white solid.

ESI MS m/e 494 M+H⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 12.25 (brs, 1 H), 8.45(t, J=5.6 Hz, 1 H), 8.17 (brs, 1 H), 8.14 (d, J=8.0 Hz, 1 H), 7.76 (t,J=8.4 Hz, 1 H), 7.42 (d, J=7.2 Hz, 1 H), 7.34 (t, J=7.6 Hz, 1 H), 7.15(s, 2 H), 4.13 (m, 1 H), 3.44 (s, 3 H), 3.39 (s, 3 H), 3.20 (m, 2 H),1.77-1.37 (m, 9 H).

Example 2335

Biphenyl-4-carboxylic acid{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-phenyl}-amide

Step A: Synthesis of (4-amino-benzyl)-carbamic acid tert-butyl ester.

A solution of 4-aminomethyl-phenylamine (12.2 g, 100 mmol) and (Boc)₂O(21.8 g, 100 mmol) in CH₂Cl₂ (100 mL) was stirred at ambient temperaturefor overnight. The mixture was concentrated and the residue was purifiedby column chromatography (silica gel, CH₂Cl₂ to 10% MeOH in CH₂Cl₂) togive (4-amino-benzyl)-carbamic acid tert-butyl ester (11.6 g, 52%) as aslightly yellow solid.

ESI MS m/e 223 M+H⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 7.27 (t, J=6.0 Hz, 1H), 6.86 (d, J=8.0 Hz, 2 H), 6.47 (d, J=6.4 Hz, 2 H), 4.89 (s, 2 H),3.91 (d, J=6.0 Hz, 2 H), 1.39 (s, 9 H).

Step B: Synthesis of biphenyl-4-carboxylic acid(4-aminomethyl-phenyl)-amide hydrochloride.

To a solution of (4-amino-benzyl)-carbamic acid tert-butyl ester (1.11g, 5 mmol), biphenyl carboxylic acid (0.99 g, 5 mmol), EDC (1.2 g, 6.25mmol), and HOAt (0.82 g, 6 mmol) in CH₂CG₂ (10 mL) was addedtriethylamine (pH=10) and the mixture was stirred at ambient temperaturefor overnight. The organic layer was washed with saturated aqueousNaHCO₃, 1 M aqueous HCl, water, dried over Na₂SO₄, filtered, andconcentrated. The residue was dissolved in 50% TFA in CH₂Cl₂ (10 mL) andthe mixture was stirred at ambient temperature. After 30 minutes, themixture was concentrated and diluted with 1 M HCl in Et₂O (5 mL). Themixture was concentrated to give biphenyl-4-carboxylic acid(4-aminomethyl-phenyl)-amide hydrochloride (828 mg, 49%).

ESI MS m/e 303 M+H⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.40 (s, 1 H), 8.34(b, 3 H), 8.07 (d, J=8.0 Hz, 2 H), 7.83-7.73 (m, 6 H), 7.51-7.38 (m, 5H), 4.0 (q, J=5.6 Hz, 2 H).

Step C: Synthesis of biphenyl-4-carboxylic acid{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-phenyl}-amide.

A mixture of (2-chloro-quinazolin-4-yl)-dimethyl-amine obtained in stepB of example 1 (42 mg, 0.2 mmol) and biphenyl-4-carboxylic acid(4-aminomethyl-phenyl)-amide hydrochloride (49 mg, 0.14 mmol) in2-propanol (1 mL) and triethylamine (200 μL) was stirred at reflux for 2days. The resulting mixture was concentrated and purified by columnchromatography (silica gel, CH₂Cl₂ to 10% 2 M NH₃/MeOH in CH₂Cl₂) togive biphenyl-4-carboxylic acid{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-phenyl}-amide (10 mg,15%) as a white solid.

ESI MS m/e 474 M+H⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.19 (s, 1 H), 8.02(d, J=7.2 Hz, 2 H), 7.86 (d, J=8.4 Hz, 1 H), 7.80 (d, J=8.4 Hz, 2 H),7.73 (d, J=7.2 Hz, 2 H), 7.68 (d, J=7.6 Hz, 2 H), 7.50-7.15 (m, 8 H),7.01 (t, J=8.4 Hz, 1 H), 4.51 (d, J=6.4 Hz, 2 H), 3.30(s, 3 H), 3.2(s, 3H).

Example 2336

cis-N²-{4-[2-(4-Bromo-2-trifluoromethoxy-benzylamino)-ethyl]-cyclohexyl}-N⁴,N⁴-dimethyl-quinazoline-2,4-diamineditrifluoro-acetic acid

Step A: Synthesis ofcis-[4-(2-benzyloxycarbonylamino-ethyl)-cyclohexyl]-carbamic acidtert-butyl ester.

To a solution of cis-[4-(2-amino-ethyl)-cyclohexyl]-carbamic acidtert-butyl ester (4.84 g, 20 mmol) in CH₂Cl₂ (50 mL) and triethylamine(3.06 mL, 22 mmol) was added benzyl chloroformate (3.13 mL, 22 mmol) andthe mixture was stirred for 4 hr. The resulting mixture was washed withwater, 1 M aqueous HCl, dried over Na₂SO₄, filtered and concentrated.The residue was purified by column chromatography (silica gel, CH₂Cl₂ to10% MeOH in CH₂Cl₂) to givecis-[4-(2-benzyloxycarbonylamino-ethyl)-cyclohexyl]-carbamic acidtert-butyl ester (5.46 g, 73%) as a colorless oil.

ESI MS m/e 377 M+H⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 7.36-7.24 (m, 5 H),7.19 (t, J=5.6 Hz, 1 H), 6.76 (d, J=6.8. Hz, 1 H), 4.91 (s, 2 H), 3.40(m, 1 H), 2.99 (m, 2 H), 1.44-1.33 (m, 20H).

Step B: Synthesis of cis-[2-(4-amino-cyclohexyl)-ethyl]-carbamic acidbenzyl ester.

A solution ofcis-[4-(2-benzyloxycarbonylamino-ethyl)-cyclohexyl]-carbamic acidtert-butyl ester (5.26 g, 14 mmol) in 50% TFA in CH₂Cl₂ (60 mL) wasstirred at ambient temperature for 1 hr. The mixture was concentratedand the residue was diluted with saturated aqueous NaHCO₃. The aqueouslayer was extracted with CH₂Cl₂ (therr times). The organic layer wasdried over Na₂SO₄ and concentrated to givecis-[2-(4-amino-cyclohexyl)-ethyl]-carbamic acid benzyl ester (3.5 g,91%) as a colorless oil.

ESI MS m/e 277 M+H⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 7.72 (b, 2 H),7.34-7.27 (m, 5 H), 7.21 (t, J=5.2 Hz, 1 H), 4.97 (s, 2 H), 3.14 (m, 1H), 2.99 (q, J=6.4 Hz, 2 H), 1.58-1.34 (m, 11 H).

Step C: Synthesis ofcis{2-[4-(4-dimethylamino-quinazolin-2-ylamino)-cyclohexyl]-ethyl}-carbamicacid benzyl ester.

A mixture of (2-chloro-quinazolin-4-yl)-dimethyl-amine obtained in stepB of example 1 (2.45 g, 10.2 mmol) andcis-[2-(4-amino-cyclohexyl)-ethyl]-carbamic acid benzyl ester (3.3 g,10.2 mmol) and triethylamine (1.65 mL, 10.2 mmol) in 2-propanol (15 mL)was heated at 170° C. for 45 min using a Smith Microwave Synthesizer.The mixture was concentrated and the residue was purified by columnchromatography (silica gel, CH₂Cl₂ to 10% 2 M NH₃/MeOH in CH₂Cl₂) togivecis{2-[4-(4-dimethylamino-quinazolin-2-ylamino)-cyclohexyl]-ethyl}-carbamicacid benzyl ester (4.48 g, 85%) as a yellow oil.

ESI MS m/e 448 M+H⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 8.07-7.20 (m, 11 H),4.98 (s, 2 H), 4.08 (m, 1 H), 3.39 (b, 6 H), 3.04 (m, 2 H), 1.7-1.3 (m,11 H).

Step D: Synthesis ofcis-N²-[4-(2-amino-ethyl)-cyclohexyl]-N⁴,N⁴-dimethyl-quinazoline-2,4-diamine.

To a solution ofcis-{2-[4-(4-dimethylamino-quinazolin-2-ylamino)-cyclohexyl]-ethyl}-carbamicacid benzyl ester (4.47 g, 10 mmol) in EtOH (20 mL) was added1,4-cyclohexadiene (20 mL) and 200 mg of 10% Pd/C. The reaction mixturewas stirred at ambient temperature for 18 hr, filtered through pad ofcelite, and concentrated. The residue was purified by columnchromatography (silica gel, 5% to 15% 2 M NH₃/MeOH in CH₂Cl₂) to givecis-N²-[4-(2-amino-ethyl)-cyclohexyl]-N⁴,N⁴-dimethyl-quinazoline-2,4-diamine(2.41 g, 77%) as a yellow oil.

ESI MS m/e 314 M+H⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 7.82 (d, J=8.0 Hz, 1H), 7.44 (t, J=6.8 Hz, 1 H), 7.27 (d, J=8.0 Hz, 1 H), 6.97 (t, J=6.8 Hz,1 H), 6.31 (brs, 1 H), 3.97 (m, 1 H), 3.37 (b, 2 H), 3.17 (s, 3 H), 3.14(s, 3 H), 2.62 (t, J=7.6 Hz, 2 H), 1.68-1.31 (m, 11 H).

Step E: Synthesis ofcis-N²-{4-[2-(4-bromo-2-trifluoromethoxy-benzylamino)-ethyl]-cyclohexyl}-N⁴,N⁴-dimethyl-quinazoline-2,4-diamineditrifluoro-acetic acid.

A solution ofcis-N²-{4-(2-amino-ethyl)-cyclohexyl]-N⁴,N⁴-dimethyl-quinazoline-2,4-diamine(31.4 mg, 0.1 mmol) and 4-bromo-2-trifluoromethoxy benzaldehyde (26.9mg, 0.1 mmol) in MeOH (1 mL) was stirred at ambient temperature. After 3hr, NaBH(OAc)₃ (85 mg, 0.4 mmol) was added and the resulting mixture wasstirred at ambient temperature for overnight. The reaction mixture wasquenched with 50% DMSO in water (2 mL). The mixture was concentrated andpurified by preparative HPLC. The pure fractions were combined andlyophilized to givecis-N²-{4-[2-(4-bromo-2-trifluoromethoxy-benzylamino)-ethyl]-cyclohexyl}-N⁴,N⁴-dimethyl-quinazoline-2,4-diamineditrifluoro-acetic acid (32.2 mg, 41%) as a white solid.

ESI MS m/e 566/568 M+H⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 12.76 (brs, 1 H),8.81 (b, 2 H), 8.43 (m, 1 H), 8.09 (d, J=8.4 Hz, 1 H), 7.71-7.56 (m, 4H), 7.35 (d, J=8.0 Hz, 1 H), 7.29 (t, J=8.0 Hz, 1 H), 4.15 (m, 3 H),3.39 (m, 6 H), 2.97 (m, 2 H), 1.67-1.30 (m, 11 H).

Example 2337

cis-2,6-Dichloro-N-{2-[4-(4-dimethylamino-quinazolin-2-ylamino)-cyclohexyl]-ethyl}-benzamidetrifluoro-acetic acid

Step A: Synthesis ofcis-2,6-dichloro-N-{2-[4-(4-dimethylamino-quinazolin-2-ylamino)-cyclohexyl]-ethyl}-benzamidetrifluoro-acetic acid.

To a solution ofcis-N²-[4-(2-amino-ethyl)-cyclohexyl]-N⁴,N⁴-dimethyl-quinazoline-2,4-diamine(31.4 mg, 0.1 mmol) and 2,6-dichlorobenzoyl chloride (20.7 mg, 0.1 mmol)in DMF (0.5 mL) was added triethylamine (20 uL, 0.14 mmol). Afterstirring the mixture at ambient temperature for 6 hr, DMSO (0.5 mL) wasadded and the mixture was purified by preparative HPLC. The purefractions were combined and lyophilized to givecis-2,6-dichloro-N-{2-[4-(4-dimethylamino-quinazolin-2-ylamino)-cyclohexyl]-ethyl}-benzamidetrifluoro-acetic acid (17.6 mg, 29%) as a white solid.

ESI MS m/e 486 M+H⁺; ¹H NMR (400 MHz, DMSO-d) δ 11.93 (brs, 1 H), 8.26(t, J=5.2 Hz, 1 H), 8.14 (d, J=8.0 Hz, 1 H), 7.95 (brs, 1 H), 7.76 (t,J=8.4 Hz, 1 H), 7.52-7.31 (m, 5 H), 4.15 (m, 1 H), 3.45 (b, 6 H), 3.29(m, 2 H), 1.76-1.31 (m, 11 H).

Example 2338

cis-N²-[4-(2-Ethoxy-benzylamino)-cyclohexylmethyl]-N⁴,N⁴-dimethyl-quinazoline-2,4-diamineditrifluoro-acetic acid

Step A: Synthesis of cis-(4-aminomethyl-cyclohexyl)-carbamic acidtert-butyl ester.

To a solution of cis-(4-carbamoyl-cyclohexyl)-carbamic acid tert-butylester obtained in step B of example 2332 (9.68 g, 40 mmol) in THF (100mL) was added a solution of 1 M BH₃ in THF (80 mL, 80 mmol) over 30 min.The mixture was stirred at reflux for 2 hr. After cooling the reactionmixture to ambient temperature, 1 M aqueous sodium hydroxide wascarefully added. The solvents were removed under reduced pressure andthe aqueous layer was extracted with CH₂Cl₂ (twice). The organic layerwas dried over sodium sulfate and concentrated under reduced pressure togive cis-(4-aminomethyl-cyclohexyl)-carbamic acid tert-butyl ester ascolorless oil (5.16 g, 57%).

ESI MS m/e 229 M+H⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 6.67 (d, J=6.8 Hz, 1H), 3.43 (m, 1 H), 2.41 (d, J=6.4 Hz, 2 H) 1.49-1.22 (m, 18 H).

Step B: Synthesis ofcis-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-cyclohexyl}-carbamicacid tert-butyl ester.

A mixture of cis-(4-aminomethyl-cyclohexyl)-carbamic acid tert-butylester (1.14 g, 5 mmol), (2-chloro-quinazoline-4-yl)-dimethyl-amineobtained in step B of example 1 (1.035 g, 5 mmol), and triethylamine(1.5 mL, 11 mmol) in 2-propanol (2.5 mL) was heated at 170° C. for 35min using a Smith Microwave Synthesizer. The mixture was concentratedand the residue was purified by column chromatography (silica gel,CH₂Cl₂ to 10% 2 M NH₃/MeOH in CH₂Cl₂) to givecis-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-cyclohexyl}-carbamicacid tert-butyl ester (1.28 g, 80%) as a white solid.

ESI MS m/e 400 M+H⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 8.04-7.06 (m, 4 H),6.77 (d, J=6.0 Hz, 1 H), 3.40-3.16 (m, 9 H), 1.70-1.37 (m, 18 H).

Step C: Synthesis ofcis-IV-(4-amino-cyclohexylmethyl)-N⁴,N⁴-dimethyl-quinazoline-2,4-diamine.

A solution ofcis-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-cyclohexyl}-carbamicacid tert-butyl ester (1.2 g, 3 mmol) in 50% TFA in CH₂Cl₂ (20 mL) wasstirred at ambient temperature. After 30 minutes, the mixture wasconcentrated and the residue was diluted with 1 M aqueous sodiumhydroxide. The aqueous layer was extracted with CH₂Cl₂ (twice). Thecombined organic layer was dried over Na₂SO₄, filtered and concentratedto givecis-N²-(4-amino-cyclohexylmethyl)-N⁴,N⁴-dimethyl-quinazoline-2,4-diamine(0.88 g, 98%) as a white solid.

ESI MS m/e 300 M+H⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 7.85 (d, J=7.6 Hz, 1H), 7.47 (t, J=6.8 Hz, 1 H), 7.27 (brs, 1 H), 7.0 (t, J=7.2 Hz, 1 H),6.66 (brs, 1 H), 3.33-3.14 (m, 9 H), 1.69-1.48 (m, 9 H).

Step D: Synthesis ofcis-N²-[4-(2-ethoxy-benzylamino)-cyclohexylmethyl]-N⁴,N⁴-dimethyl-quinazoline-2,4-diamineditrifluoro-acetic acid.

A solution ofcis-N²-(4-amino-cyclohexylmethyl)-N⁴,N⁴-dimethyl-quinazoline-2,4-diamine(30 mg, 0.1 mmol) and 2-ethoxy benzaldehyde (15 mg, 0.1 mmol) in MeOH (1mL) was stirred at ambient temperature. After 3 hr, NaBH(OAc)₃ (85 mg,0.4 mmol) was added and the mixture was stirred at ambient temperaturefor overnight. The resulting mixture was quenched with 50% DMSO in water(2 mL) and the solution was purified by preparative HPLC. The purefractions were combined and lyophilized to givecis-N²-[4-(2-ethoxy-benzylamino)-cyclohexylmethyl]-N⁴,N⁴-dimethyl-quinazoline-2,4-diamineditrifluoro-acetic acid (33 mg, 50%) as a white solid.

ESI MS m/e 434 M+H⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 13.03 (brs, 1 H), 8.79(brs, 1 H), 8.49 (m, 2 H), 8.15 (d, J=8.4 Hz, 1 H), 7.77 (t, J=7.6 Hz, 1H), 7.40-7.33 (m, 4 H), 7.07 (d, J=7.6 Hz, 1 H), 6.99 (t, J=7.2 Hz, 1H), 4.11-4.06 (m, 4 H), 3.47-3.41 (m, 8 H), 3.15 (m, 1 H), 1.90-1.60 (m,9 H), 1.37 (t, J=7.2 Hz, 3 H).

Example 2339

cis-3,5-Dichloro-N-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-cyclohexyl}-benzamidetrifluoro-acetic acid

Step A: Synthesis ofcis-3,5-dichloro-N-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-cyclohexyl}-benzamidetrifluoro-acetic acid.

A solution ofcis-N²-(4-amino-cyclohexylmethyl)-N⁴,N⁴-dimethyl-quinazoline-2,4-diamine(30 mg, 0.1 mmol) and 3,5-dichlorobenzoylchloride (20.9 mg, 0.1 mmol)and pyridine (12 μL, 0.25 mmol) in DMSO (1 mL) was stirred at ambienttemperature for overnight. The mixture was purified by preparative HPLC.The pure fractions were combined and lyophilized to givecis-3,5-dichloro-N-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-cyclohexyl}-benzamidetrifluoro-acetic acid. (18 mg, 31%) as a white solid.

ESI MS m/e 472 M+H⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 12.13 (brs, 1 H), 8.34(d, J=7.2 Hz, 1 H), 8.15 (d, J=8.8 Hz, 1 H), 8.06 (brs, 1 H), 7.82-7.73(m, 4 H), 7.45 (d, J=7.6 Hz, 1 H), 7.36 (t, J=7.6 Hz, 1 H), 3.9 (m, 1H), 3.47-3.25 (m, 8 H), 1.83-1.56 (m, 9 H).

Example 2340

trans-N²-{4-[(2,3-Dimethoxy-benzylamino)-methyl]-cyclohexyl}-N⁴,N⁴-dimethyl-quinazoline-2,4-diamineditrifluoro-acetic acid

Step A: Synthesis oftrans-4-(tert-butoxycarbonylamino-methyl)-cyclohexanecarboxylic acid.

To a solution of trans-4-amino-cyclohexanecarboxylic acid (37.7 g, 0.24mol) in a mixture of dioxane (250 ml) and water (200 ml) cooled in anice bath were added 1 M aqueous sodium hydroxide (10.07 g, 0.25 mol) and(Boc)₂O (57.6 g, 0.26 mol). The reaction mixture was stirred at ambienttemperature. After 3 hr, the mixture was concentrated and the residuewas dissolved in water. The aqueous layer was washed with Et₂O (3times). The aqueous layer was cooled in an ice bath and acidified with 1M aqueous HCl (pH=2) and the resulting white precipitate was dried togive trans-4-(tert-butoxycarbonylamino-methyl)-cyclohexanecarboxylicacid (47.4 g, 76.8%) as a white solid.

ESI MS m/e 258 M+H⁺; ¹H NMR (400 MHz, CDCl₃) δ 11.95 (brs, 1 H), 6.79(t, J=6.0 Hz, 1 H), 2.76 (t, J=6.0 Hz, 2 H), 2.11 (m, 1 H), 1.87 (m, 2H), 1.69 (m, 2 H), 1.36 (s, 9 H), 1.27(m, 3 H), 0.9 (m, 2 H).

Step B: Synthesis oftrans-[4-(tert-butoxycarbonylamino-methyl)-cyclohexyl]-carbamic acidbenzyl ester.

To a solution oftrans-4-(tert-butoxycarbonylamino-methyl)-cyclohexanecarboxylic acid(46.9 g, 0.18 mol) in benzene (300 mL) were added triethylamine (24.2 g,0.24 mol) and diphenylphosphoryl azide (55.9 g, 0.20 mol). The reactionmixture was stirred at 80° C. for 1 hr. To the mixture was added benzylalcohol (25.9 g, 0.24 mol) and stirred at 100° C. for 4 hr. The mixturewas subsequently cooled to ambient temperature for overnight,concentrated, and the resulting pale orange solid dissolved in EtOAc.The organic layer was washed with water (three times), concentrated, andthe residue was purified by column chromatography (silica gel, 50% EtOAcin hexane) to givetrans-[4-(tert-butoxycarbonylamino-methyl)-cyclohexyl]-carbamic acidbenzyl ester (66.7 g, 100%) as a white solid.

ESI MS m/e 363 M+H⁺; ¹H NMR (400 MHz, CDCl₃) δ 7.24-7.23 (m, 5 H), 5.06(s, 2 H), 4.57 (m, 2 H), 3.44 (brs, 1 H), 2.97 (t, J=6.4 Hz, 2 H), 2.04(m, 2 H), 1.79 (m, 2 H), 1.43 (s, 9 H), 1.08-0.76 (m, 5 H).

Step C: Synthesis of trans-(4-amino-cyclohexylmethyl)-carbamic acidtert-butyl ester.

To a solution oftrans-[4-(tert-butoxycarbonylamino-methyl)-cyclohexyl]-carbamic acidbenzyl ester (5.32 g, 0.015 mol) in EtOH (200 mL) was added 10% Pd/C (50mg). The mixture was stirred at ambient temperature under hydrogenatmosphere for 4 hr. The resulting mixture was filtered through a pad ofcelite and concentrated. The residue was purified by columnchromatography (silica gel, 3% 2 M NH₃/MeOH in CH₂Cl₂) to givetrans-(4-amino-cyclohexylmethyl)-carbamic acid tert-butyl ester as acolorless solid (3.197 g, 95.4%).

ESI MS m/e 229 M+H⁺; ¹H NMR (400 MHz, CDCl₃) δ 8.44 (brs, 1 H), 4.59 (b,1 H), 2.96 (m, 2 H), 2.08 (m, 2 H), 1.83 (m, 2 H), 1.43 (s, 9 H), 1.08(m, 5 H).

Step D: Synthesis oftrans-N²-(4-aminomethyl-cyclohexyl)-N⁴,N⁴-dimethyl-quinazoline-2,4-diamineditrifluoro-acetic acid.

A mixture of trans-(4-amino-cyclohexylmethyl)-carbamic acid tert-butylester (0.24 g, 1 mmol) and (2-chloro-quinazolin-4-yl)-dimethyl-amineobtained in step B of example 1 (0.32 g, 1.4 mmol) in 2-propanol (5 mL)was heated to 170° C. for 30 min using a Smith Microwave Synthesizer.This procedure was repeated 19 times. The reaction mixtures werecombined and purified by column chromatography (silica gel) to give 1.13g of a yellow solid. The yellow solid was dissolved in 50% TFA in CH₂Cl₂(20 mL) and the mixture was stirred at ambient temperature. After 10hours, the mixture was concentrated and the residue was purified bypreparative HPLC. The pure fractions were combined and lyophilized togivetrans-N²-(4-aminomethyl-cyclohexyl)-N⁴,N⁴-dimethyl-quinazoline-2,4-diamineditrifluoro-acetic acid (0.49 g, 5%) as a white solid.

ESI MS m/e 300 M+H⁺; ¹H NMR (400 MHz, CDCl₃) δ 9.16 (d, J=5.6 Hz, 1 H),8.11 (m, 2 H), 7.86 (d, J=8.0 Hz, 1 H), 7.51 (t, J=7.6 Hz, 1 H), 7.41(d, J=8.0 Hz, 1 H), 7.18 (t, J=6.8 Hz, 1 H), 3.8 (brs, 1 H), 3.47 (s, 6H), 2.10 (m, 2 H), 1.92 (m, 2 H), 1.42-1.12 (m, 5 H).

Step E: Synthesis oftrans-N²-{4-[(2,3-dimethoxy-benzylamino)-methyl]-cyclohexyl}-N⁴,N⁴-dimethyl-quinazoline-2,4-diamineditrifluoro-acetic acid.

A mixture of 2,3-dimethoxy benzaldehyde (15 mg, 0.09 mmol),trans-N²-(4-aminomethyl-cyclohexyl)-N⁴,N⁴-dimethyl-quinazoline-2,4-diamineditrifluoro-acetic acid (28 mg, 0.053 mmol), NaBH(OAc)₃ (76 mg, 0.36mmol), and MeOH (2 mL) was heated at 100° C. for 40 seconds using aSmith Microwave Synthesizer. The resulting mixture was purified bypreparative HPLC. The pure fractions were combined and lyophilized togivetrans-N²-{4-[(2,3-dimethoxy-benzylamino)-methyl]-cyclohexyl}-N⁴,N⁴-dimethyl-quinazoline-2,4-diamineditrifluoro-acetic acid (10.2 mg, 28%).

ESI MS m/e 450 M+H⁺; ¹H NMR (400 MHz, CDCl₃) δ 9.68 (d, J=6.0 Hz, 1 H),9.41 (brs, 1 H), 7.85 (d, J=7.6 Hz, 1 H), 7.52 (t, J=7.2 Hz, 1 H), 7.46(d, J=8.0 Hz, 1 H), 7.19 (t, J=7.2 Hz, 1 H), 7.09 (t, J=8.0 Hz, 1 H),6.98 (d, J=7.2 Hz, 1 H), 6.90 (d, J=7.6 Hz, 1 H), 4.16 (s, 2 H), 3.96(s, 3 H), 3.87 (s, 3 H), 3.75 (m, 1 H), 3.47 (m, 6 H), 2.80 (m, 2 H),2.11 (m, 2 H), 1.86 (m, 2 H), 1.48-1.50 (m, 5 H).

Example 2341

cis-N²-[4-(3,5-Dichloro-benzylamino)-cyclohexyl]-N⁴,N⁴-dimethyl-quinazoline-2,4-diamineditrifluoro-acetic acid

Step A: Synthesis ofcis-(4-tert-butoxycarbonylamino-cyclohexyl)-carbamic acid benzyl ester.

To a suspension of cis-4-tert-butoxycarbonylamino-cyclohexanecarboxylicacid (50.0 g, 206 mmol) in benzene were added triethylamine (26.9 g, 266mmol) and phosphorazidic acid diphenyl ester (62.2 g, 226 mmol). Thereaction mixture was stirred at 80° C. for 1 hr. Benzyl alcohol (31.4 g,290 mmol) was added and the mixture was stirred at reflux for 24 hr. Thereaction mixture was concentrated and the residue was dissolved in EtOAcand H₂O. The organic layer was separated and the aqueous layer wasextracted with EtOAc (twice). The combined organic layer was dried overMgSO₄, filtered, concentrated, and purified by flash chromatography(silica gel, 30% EtOAc in hexane) to givecis-(4-tert-butoxycarbonylamino-cyclohexyl)-carbamic acid benzyl ester(54.1 g, 76%) as a colorless oil.

ESI MS m/e 349 M+H⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 7.34-7.28 (m, 5 H),7.12 (d, J=5.6 Hz, 1 H), 6.62 (brs, 1 H), 4.98 (s, 2 H), 3.39-3.37 (m, 2H), 1.60-1.45 (m, 8 H), 1.37 (s, 9 H).

Step B: Synthesis of cis-(4-amino-cyclohexyl)-carbamic acid tert-butylester.

Using the procedure for the step C of example 2340, the title compoundwas obtained

ESI MS m/e 215 M+H⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 6.60 (d, J=6.0 Hz, 1H), 3.30-3.28 (m, 1 H), 2.74 (s, 1 H), 1.59-1.51 (m, 2 H), 1.45-1.37 (m,15 H).

Step C: Synthesis ofcis-[4-(4-dimethlyamino-quinazolin-2-ylamino)-cyclohexyl]-carbamic acidtert-butyl ester.

A solution of cis-(4-amino-cyclohexyl)-carbamic acid tert-butyl ester(0.5 g, 2.3 mmol), (2-chloro-quinazolin-4-yl)-dimethly-amine obtained instep B in example 1 (0.53, 2.6 mmol), diisopropylethylamine (1.22 mL,7.0 mmol) and 2-propanol (1.0 mL) was heated using a Smith MicrowaveSynthesizer at 170° C. for 1 hour. This reaction procedure was repeated39 more times and the resulting reaction mixtures were combined. Themixture was concentrated and the residue was purified by columnchromatography (silica gel, 2% to 4% 2 M NH₃/MeOH in CH₂Cl₂) to givecis-[4-(4-dimethlyamino-quinazolin-2-ylamino)-cyclohexyl]-carbamic acidtert-butyl ester (22.1 g, 0.057 mol, 61%) as a colorless oil.

ESI MS m/e 386 M+H⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 7.85 (d, J=8.0 Hz, 1H), 7.47 (t, J=8.4 Hz, 1 H), 7.27 (d, J=8.0 Hz, 1 H), 7.00 (t, J=7.6 Hz,1 H), 6.60 (brs, 1 H), 6.18 (brs, 1 H), 3.89-3.88 (m, 1 H), 3.39 (brs, 1H), 3.19 (s, 6 H), 1.77-1.71 (m, 2 H), 1.68-1.52(m, 6 H), 1.38(s, 9 H).

Step D: Synthesis ofcis-N²-(4-amino-cyclohexyl)-N⁴,N⁴-dimethyl-quinazolin-2,4-diamine.

Using the procedure for the step C of example 2338, the title compoundwas obtained.

ESI MS m/e 286 M+H⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 7.84 (d, J=8.4 Hz, 1H), 7.45 (t, J=6.8 Hz, 1 H), 7.26 (d, J=8.4 Hz, 1 H), 6.99 (t, J=7.6 Hz,1 H), 6.20 (brs, 1 H), 3.90-3.89 (m, 1 H), 3.18 (s, 6 H), 2.79 (s, 1 H),1.74-1.71 (m, 2 H), 1.57-1.41 (m, 8 H).

Step E: Synthesis ofcis-N²-[4-(3,5-dichloro-benzylamino)-cyclohexyl]-N⁴,N⁴-dimethyl-quinazoline-2,4-diamineditrifluoro-acetic acid.

To a solution ofcis-N²-(4-amino-cyclohexyl)-N⁴,N⁴-dimethyl-quinazolin-2,4-diamine (31.4mg, 0.11 mmol) in MeOH (0.5 mL) was added 3,5-dichlorobenzaldehyde (17.5mg, 0.10 mmol). The mixture was stirred at ambient temperature for 0.5hr and sodium triacetoxyborohydride (85 mg, 0.40 mmol) was added. Themixture was stirred for overnight and the reaction was quenched with 50%DMSO in water (1.0 mL). The mixture was purified by preparative HPLC.The pure fractions were combined and lyophilized to givecis-M²-[4-(3,5-dichloro-benzylamino)-cyclohexyl]-N⁴,N⁴-dimethyl-quinazoline-2,4-diamineditrifluoro-acetic acid (23 mg, 0.041 mmol, 37%) as a white solid.

ESI MS m/e 444 M+H⁺, ¹H NMR (400 MHz, DMSO-d₆) δ 13.55 (s, 1 H), 8.90(brs, 3 H), 8.17 (d, J=8.0 Hz, 1 H), 7.79 (t, 7.6 Hz, 1 H), 7.68 (s, 1H), 7.61 (s, 2 H), 7.41 (d, J=7.6 Hz, 1 H), 7.36 (t, J=7.6 Hz, 1 H),4.23 (s, 2 H), 4.07 (s, 1 H), 3.48 (s, 6 H), 2.00-1.92 (m, 4 H),1.82-1.74 (m, 4 H).

Example 2342

cis-N-[4-(4-Dimethylamino-quinazolin-2-ylamino)-cyclohexyl]-3,4-difluoro-benzamidetrifluoro-acetic acid

Step A: Synthesis ofcis-N-[4-(4-dimethylamino-quinazolin-2-ylamino)-cyclohexyl]-3,4-difluoro-benzamidetrifluoro-acetic acid.

Using the procedure for the step A of example 2333, the title compoundwas obtained.

ESI MS m/e 426 M+H⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 12.46 (brs, 1 H), 8.36(s, 1 H), 8.15 (d, J=8.0 Hz, 1 H), 7.97 (brs, 1 H), 7.94-7.89 (m, 1 H),7.77-7.73 (m, 2 H), 7.56-7.49 (m, 1 H), 7.41 (brs, 1 H), 7.36 (t, J=7.6Hz, 1 H), 4.07 (m, 1 H), 3.87 (m, 1 H), 3.47 (brs, 6 H), 1.89 (m, 2 H),1.74 (m, 6 H).

Example 2343

cis-4-Dimethlyamino-N-[4-(4-dimethlyamino-quinazolin-2-ylamino)-cyclohexyl]-benzamideditrifluoro-acetic acid

Step A: Synthesis ofcis-4-dimethlyamino-N-[4-(4-dimethlyamino-quinazolin-2-ylamino)-cyclohexyl]-benzamideditrifluoro-acetic acid

To a solution of 4-dimethylaminobenzoic acid (16.5 mg, 0.10 mmol) in DMF(0.5 mL) were added HATU (45.6 mg, 0.12 mmol), diisopropylethylamine(34.8 uL, 0.20 mmol), andcis-N²-(4-amino-cyclohexyl)-N⁴,N⁴-dimethyl-quinazolin-2,4-diamineobtained in step D of example 2341 (28.5 mg, 0.10 mmol) and stirred atambient temperature for overnight. The resulting mixture was dilutedwith DMSO (0.5 mL) and purified by preparative HPLC. The pure fractionscombined and lyophilized to givecis-4-dimethlyamino-N-[4-(4-dimethlyamino-quinazolin-2-ylamino)-cyclohexyl]-benzamideditrifluoro-acetic acid (34.1 mg, 0.052 mmol, 52%) as a white solid.

ESI MS m/e 433 M+H⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 12.73 (s, 1 H), 8.34(s, 1 H), 8.16 (d, J=8.0 Hz, 1 H), 7.78-7.70 (m, 4 H), 7.43 (d, J=7.6Hz, 1 H), 7.35 (t, J=8.0 Hz, 1 H), 6.67 (d, J=8.8 Hz, 2 H), 4.05 (m, 1H), 3.86 (m, 1 H), 3.47 (s, 6 H), 2.95 (s, 3 H), 2.53 (s, 3 H), 1.91 (m,2 H), 1.75-1.72 (m, 6 H).

Example 2344

trans-4-Bromo-N-[4-(4-dimethlyamino-quinazolin-2-ylamino)-cyclohexyl]-2-trifluoromethoxy-benzenesulfonamide

Step A: Synthesis of trans-(4-amino-cyclohexyl)-carbamic acid tert-butylester.

To a solution of trans-1,4-diamino-cyclohexane (10 g, 0.088 mol) in1,4-dioxane (400 mL) was added a solution of (Boc)₂O (4.78 g, 0.022 mol)in 1,4-dioxane (100 ml) over 30 min. The mixture was stirred at ambienttemperature for overnight and then the dioxane was removed in vacuo. Theresulting precipitate was dissolved in H₂O (500 mL) and left to sit for1 hour. During this time, the di-Boc-protected diamino-cyclohexane fellout as a white crystalline precipitate. This was subsequently filteredfrom the aqueous solvent. The aqueous layer was extracted with EtOAc(three times). The organic layers were combined and washed with H₂O. Theorganic layer was dried over MgSO₄ and concentrated to givetrans-(4-amino-cyclohexyl)-carbamic acid tert-butyl ester (4 g, 0.019mol, 85%).

ESI MS m/e 215 M+H⁺; ¹H NMR (400 MHz, DMSO-d₆) 66.63 (d, J=8.0 Hz, 1 H),3.11-3.09 (m, 1 H), 2.44-2.37 (m, 1 H), 1.70-1.67 (m, 4 H), 1.41-1.31(m, 11 H), 1.20-0.95 (m, 4 H).

Step B: Synthesis oftrans-[4-(4-bromo-2-trifluoromethoxy-benzenesulfonylamino)-cyclohexyl]-carbamicacid tert-butyl ester.

To a solution of trans-(4-amino-cyclohexyl)-carbamic acid tert-butylester (1 g, 0.0047 mol) in CH₂Cl₂ were added diisopropylethylamine (1.63mL, 0.0093 mol) and 4-bromo-2-trifluoromethoxy-benzenesulfonyl chloride(1.03 mL, 0.0051 mol). The reaction mixture was stirred at ambienttemperature for 1 hr and then washed with water. The aqueous layer wasextracted with CH₂Cl₂ (twice), the organic layers were combined, driedover MgSO₄, and concentrated. The resulting precipitate wasrecrystallized with CH₂Cl₂ and hexanes to givetrans-[4-(4-bromo-2-trifluoromethoxy-benzenesulfonylamino)-cyclohexyl]-carbamicacid tert-butyl ester (2.39 g, 0.0046 mol, 99%).

ESI MS m/e 517 M+H⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 7.99 (d, J=7.6 Hz, 1H), 7.85 (d, J=8.0 Hz, 1 H), 7.79-7.77 (m, 1 H), 6.67 (d, J=8.0 Hz, 1H), 3.14-2.94 (m, 2 H), 1.70-1.60 (m, 4 H), 1.34 (s, 9 H), 1.30-1.18 (m,2 H), 1.14-1.03 (m, 2 H).

Step C: Synthesis oftrans-N-(4-amino-cyclohexyl)-4-bromo-2-trifluoromethoxy-benzenesulfonamide.

Using the procedure for the step C of example 2338, the title compoundwas obtained.

ESI MS m/e 417/419 M+H⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 7.85 (d, J=8.4 Hz,1 H), 7.79-7.76 (m, 3 H), 3.32 (brs, 2 H), 3.03-2.95 (m, 1 H), 2.41-2.36(m, 1 H), 1.67-1.57 (m, 4 H), 1.28-1.18 (m, 2 H), 0.99-0.89 (m, 2 H).

Step D: Synthesis oftrans-4-bromo-N-[4-(4-dimethlyamino-quinazolin-2-ylamino)-cyclohexyl]-2-trifluoromethoxy-benzenesulfonamide.

To a solution oftrans-N-(4-amino-cyclohexyl)-4-bromo-2-trifluoromethoxy-benzenesulfonamide(100 mg, 0.24 mmol) in 2-propanol (0.5 mL) was added(2-chloro-quinazolin-4-yl)-dimethly-amine obtained in step B of example1 (54.7 mg, 0.26 mmol). The mixture was heated using a Smith MicrowaveSynthesizer at 170° C. for 15 min. The mixture was concentrated and theresidue was purified by chromatography (2% to 4% 2 M NH₃/MeOH in CH₂Cl₂)to givetrans-4-bromo-N-[4-(4-dimethlyamino-quinazolin-2-ylamino)-cyclohexyl]-2-trifluoromethoxy-benzenesulfonamide(42 mg, 0.71 mmol, 30%) as a white solid.

ESI MS m/e 588/590 M+H⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 8.02 (d, J=7.6 Hz,1 H), 7.88 (d, J=8.4 Hz, 1 H), 7.82-7.77 (m, 3 H), 7.45-7.41 (m, 1 H),7.25-7.41 (m, 1 H), 6.99 (t, J=7.2 Hz, 1 H), 6.37 (brs, 1 H), 3.68-3.67(m, 1 H), 3.16 (s, 6 H), 3.09-3.02 (m, 1 H), 1.89-1.86 (m, 2 H),1.69-1.67 (m, 2 H), 1.40-1.17 (m, 4 H).

Example 2345

trans-4′-Fluoro-biphenyl-4-carboxylic acid[4-(4-dimethlyamino-quinazolin-2-ylamino)-cyclohexyl]-amide

Step A: Synthesis of 4′-fluoro-biphenyl-4-carboxylic acid.

To a solution of 4-bromobenzoic acid (5 g, 0.025 mol) in THF (150 mL)under an atmosphere of argon were added tetrakis(triphenylphosphine)palladium(0) (862 mg, 0.75 mmol), 2 M aqueous Na₂CO₃ (30 mL), and asolution 4-fluorophenyboronic acid (3.48 g, 0.025 mol) in a minimalamount of ethanol (˜10 mL). The resulting reaction mixture was stirredat reflux under an argon atmosphere for overnight. The reaction mixturewas cooled to ambient temperature and acidified with addition of 1 M HClaqueous. The aqueous layer was extracted with Et₂O (three times). Theorganic layers were combined, dried over MgSO₄, filtered andconcentrated. The resulting precipitate was crystallized in Et₂O andhexane to give 4′-fluoro-biphenyl-4-carboxylic acid (4.4 g, 0.020 mol,82%) as a white solid.

¹H NMR (400 MHz, DMSO-d₆) δ 12.96 (s, 1 H), 8.00-7.98 (m, 2 H),7.78-7.75 (m, 4 H), 7.34-7.31 (m, 2 H).

Step B: Synthesis oftrans-[4-(4-dimethlyamino-quinazolin-2-ylamino)-cyclohexyl]-carbamicacid tert-butyl ester.

Using the procedure for the step D of example 2344, the title compoundwas obtained.

ESI MS m/e 386 M+H⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 7.83 (d, J=8.0 Hz, 1H), 7.46 (t, J=6.8 Hz, 1 H), 7.27-7.25 (m, 1 H), 6.99 (t, J=7.2 Hz, 1H), 6.71 (d, J=8.4 Hz, 1 H), 6.38 (brs, 1 H), 3.72 (m, 1 H), 3.17 (s, 6H), 1.92-1.90 (m, 2 H), 1.79-1.76 (m, 2 H), 1.37 (s, 9 H), 1.34-1.23 (m,4 H).

Step C: Synthesis of trans-4′-fluoro-biphenyl-4-carboxylic acid[4-(4-dimethlyamino-quinazolin-2-ylamino)-cyclohexyl]-amide.

To a solution oftrans-[4-(4-dimethlyamino-quinazolin-2-ylamino)-cyclohexyl]-carbamicacid tert-butyl ester (0.76 g, 0.20 mmol) in CH₂Cl₂ (20 mL) was addedTFA (304 μL, 0.39 mmol). The solution was stirred at ambient temperaturefor 4 hr. The resulting mixture was concentrated and the residue wasdissolved in CH₂Cl₂. The organic layer was washed with a dilute aqueousNaOH and aqueous NaHCO₃ solution. The aqueous layer was extracted withCH₂Cl₂ (twice) and the organic layers combined, dried over MgSO₄, andconcentrated. To a solution of the residue (0.1 g) and4-fluoro-biphenyl-4-carboxylic acid (76 mg, 0.35 mmol) in CH₂Cl₂ wereadded HOAt (62 mg, 0.46 mmol), WSC—HCl (87 mg, 0.46 mmol), anddiisopropylethylamine (31 uL, 0.18 mmol). The mixture was stirred for 1hr at ambient temperature and the reaction was quenched with water. Theaqueous layer was extracted with CH₂Cl₂ (twice). The organic layers werecombined, dried over MgSO₄, concentrated and the residue purified bycolumn chromatography (silica gel, 2% to 4% 2 M NH₃/MeOH in CH₂Cl₂) togive trans-4′-fluoro-biphenyl-4-carboxylic acid[4-(4-dimethlyamino-quinazolin-2-ylamino)-cyclohexyl]-amide (35 mg,0.072, 21%) as a white solid.

ESI MS m/e 484 M+H⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 8.30 (brs, 1 H), 8.12(brs, 2 H), 7.92 (d, J=8.4 Hz, 2 H), 7.77-7.72 (m, 5 H), 7.44 (brs, 1H), 7.34-7.28 (m, 3 H), 3.82 (brs, 2 H), 3.47 (brs, 6 H), 2.04 (m, 2 H),1.94 (m, 2 H), 1.54-1.48 (m, 4 H).

Example 2346

cis-N²-[4-(4-Bromo-2-trifluoromethoxy-benzylamino)-cyclohexyl]-N⁴-tert-butyl-quinazoline-2,4-diamineditrifluoro-acetic acid

Step A: Synthesis of tert-butyl-(2-chloro-quinazolin-4-yl)-amine.

To a solution of 2,4-dichloro-quinazoline obtained in step B of example1 (4 g, 20 mmol) in THF (50 mL) were added tert-butyl amine (2.15 mL,20.5 mmol) and diisopropylethylamine (3.5 mL, 21 mmol). The mixture wasstirred at ambient temperature for 2 hr. The mixture was concentratedand the residue was dissolved in EtOAc. The organic layer was washedwith water, dried over Na₂SO₄, and filtered. The mixture wasconcentrated to give tert-butyl-(2-chloro-quinazolin-4-yl)-amine as awhite solid (3 g, 64%).

ESI MS m/e 236 M+H⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 8.40 (d, J=8.4 Hz, 1H), 7.75-7.36 (m, 2 H), 7.58 (d, J=8.4 Hz, 1 H), 7.48 (t, J=7.2 Hz, 1H), 1.52 (s, 9 H).

Step B: Synthesis ofcis-N²-(4-amino-cyclohexyl)-N²-tert-butyl-quinazoline-2,4-diamine.

To a suspension of cis-(4-amino-cyclohexyl)-carbamic acid tert-butylester (122 mg, 0.57 mmol) in 2-propanol (2 mL) were addedtert-butyl-(2-chloro-quinazolin-4-yl)-amine (100 mg, 0.42 mmol) anddiisopropylethylamine (180 μL, 1 mmol) and the mixture was heated at170° C. for 1 hr using a Smith Microwave Synthesizer. The resultingsolution was concentrated and purified by column chromatography (silicagel, 3% MeOH in CH₂Cl₂) to give[4-(4-tert-butylamino-quinazolin-2-ylamino)-cyclohexyl]-carbamic acidtert-butyl ester (112 mg, 65%) as a yellow solid. To a suspension ofcis-[4-(4-tert-butylamino-quinazolin-2-ylamino)-cyclohexyl]-carbamicacid tert-butyl ester (95 mg, 0.23 mmol) in CH₂Cl₂ (3 mL) was addedtrifluoroacetic acid (2 mL) dropwise. The reaction mixture was stirredat ambient temperature for 2 hr. The solution was concentrated,alkalized with saturated aqueous NaHCO₃ and 1 M aqueous sodium hydroxide(pH=9), and the aqueous layer was extracted with CH₂Cl₂ (three times).The combined organic layer was dried over MgSO₄, filtered, andconcentrated. The solid was collected by filtration to givecis-N²-(4-amino-cyclohexyl)-N-tert-butyl-quinazoline-2,4-diamine (44.6mg, 53%) as a yellow solid.

ESI MS m/e 314 M+H⁺; ¹H NMR (400 MHz, CDCl₃) δ 7.48 (t, J=6.8 Hz, 1 H),7.38 (m, 2 H), 7.04 (t, J=8.0 Hz, 1 H), 5.42 (brs, 1 H), 4.15 (m, 1 H),2.85 (m, 1 H), 1.2-1.9 (m, 17 H).

Step C: Synthesis ofcis-N²-[4-(4-bromo-2-trifluoromethoxy-benzylamino)-cyclohexyl]-N⁴-tert-butyl-quinazoline-2,4-diamineditrifluoro-acetic acid.

Using the procedure for the step C of example 2341, the title compoundwas obtained.

ESI MS m/e 566 M+H⁺; ¹H NMR (400 MHz, CDCl₃) δ 9.36 (d, J=8.0 Hz, 1 H),7.67-7.64 (m, 2 H), 7.53-7.48 (m, 3 H), 7.43 (s, 1 H), 7.33 (m, 1 H),6.17 (s, 1 H), 4.45 (m, 1 H), 4.28 (s, 2 H), 3.35 (m, 1 H), 2.14-1.6 (m,17 H).

Example 2347

4-Bromo-N-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-benzyl}-2-trifluoromethoxy-benzenesulfonamide

Step A: Synthesis of{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-benzyl}-carbamic acidtert-butyl ester.

Using the procedure for the step D of example 2330, the title compoundwas obtained.

ESI MS m/e 377 M+H⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 8.38 (brs, 1 H), 8.08(brs, 1 H), 7.70 (brs, 1 H), 7.47 (brs, 1 H), 7.36 (t, J=6.2 Hz, 1 H),7.30 (d, J=8.0 Hz, 3 H), 7.16 (d, J=7.6 Hz, 2 H), 4.60 (d, J=6.4 Hz, 2H), 4.07 (d, J=6.0 Hz, 2 H), 3.39 (s, 6 H), 1.37 (s, 9 H).

Step B: Synthesis ofN²-(4-aminomethyl-benzyl)-N⁴,N⁴-dimethyl-quinazoline-2,4-diaminehydrochloride.

To a cooled solution of{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-benzyl}-carbamic acidtert-butyl ester (3.90 g, 9.57 mmol) in MeOH was added 1 M HCl in Et₂O(67.0 ml, 67.0 mmol) and the solution was stirred for overnight. Theresulting mixture was concentrated to giveN²-(4-aminomethyl-benzyl)-N⁴,N⁴-dimethyl-quinazoline-2,4-diaminehydrochloride as a white crystalline solid (3.48 g, 95.6%).

ESI MS m/e 308.2 M+H⁺; ¹H NMR (400 MHz, CD₃OD) δ 8.16 (d, J=7.2 Hz, 1H), 7.75 (brs, 1 H), 7.48 (m, 5 H), 7.39 (brs, 1 H), 4.76 (s, 2 H), 4.12(s, 2 H), 3.51 (m, 6 H).

Step C: Synthesis of4-bromo-N-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-benzyl}-2-trifluoromethoxy-benzenesulfonamide.

A solution ofN²-(4-aminomethyl-benzyl)-N⁴,N⁴-dimethyl-quinazoline-2,4-diaminehydrochloride (50.0 mg, 0.131 mmol),4-bromo-2-trifluoromethoxy-benzenesulfonyl chloride (53.3 mg, 0.157mmol) and diisopropylethylamine (91 μl, 0.524 mmol) in 2-propanol (1.5mL) was stirred at ambient temperature for 2 hr. The resulting mixturewas concentrated, and the residue was purified by column chromatography(silica gel, 10% MeOH in CH₂Cl₂) to give4-bromo-N-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-benzyl}-2-trifluoromethoxy-benzenesulfonamideas a white crystalline compound (40 mg, 50%).

ESI MS m/e 612 M+H⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 8.51 (t, J=6.4 Hz, 1H), 8.06 (brs, 1 H), 7.76-7.67 (m, 4 H), 7.54-7.41 (m, 2 H), 7.24 (d,J=7.6 Hz, 3 H), 7.14 (d, J=8.0 Hz, 2 H), 4.56 (d, J=6.0 Hz, 2 H), 4.08(d, J=6.0 Hz, 2 H), 3.36 (s, 6 H).

Example 2348

4-bromo-N-[4-(4-dimethylamino-quinazolin-2-ylamino)-phenyl]-2-trifluoromethoxy-benzenesulfonamide

Step A: Synthesis of (4-amino-phenyl)-carbamic acid tert-butyl ester.

Using the procedure for the step A of example 2344, the title compoundwas obtained

ESI MS m/e 209 M+H⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 8.75 (s, 1 H), 7.03 (d,J=7.6 Hz, 2 H), 6.43 (dt, J=9.5, 2.7 Hz, 2 H), 4.71 (s, 2 H), 1.43 (s, 9H).

Step B: Synthesis ofN²-(4-amino-phenyl)-N⁴,N⁴-dimethyl-quinazoline-2,4-diaminehydrochloride.

A mixture of (2-chloro-quinazolin-4-yl)-dimethyl-amine obtained in stepB of example 1 (0.5 g, 2.6 mmol) and (4-amino-phenyl)-carbamic acidtert-butyl ester (0.5 g, 2.6 mmol) in CH₂Cl₂ (2 mL) was heated by SmithSynthesizer at 130° C. for 20 min. The mixture was concentrated to give[4-(4-dimethylamino-quinazolin-2-ylamino)-phenyl]-carbamic acidtert-butyl ester as a pale yellow solid (0.86 g, 87%). The reaction wasrepeated six times, and the total product combined was 8.5 g. To asolution of above product (8.5 g, 22.4 mmol) in MeOH (250 mL) was added4 M HCl in dioxane (8.4 ml, 33.6 mmol) dropwise, and the mixture wasstirred at ambient temperature for overnight. The mixture wasconcentrated to giveN²-(4-amino-phenyl)-N⁴,N⁴-dimethyl-quinazoline-2,4-diamine hydrochlorideas a pale pink solid (6.2 g, 87.5%).

ESI MS m/e 280 M+H⁺; ¹H NMR (400 MHz, D₂O) δ 7.84 (d, J=8.8 Hz, 1 H),7.54 (td, J=7.8, 1.2 Hz, 1 H), 7.46 (dt, J=9.5, 2.7 Hz, 2 H), 7.27-7.16(m, 4 H), 3.35 (b, 3 H), 3.12 (b, 3 H).

Step C: Synthesis of4-bromo-N-[4-(4-dimethylamino-quinazolin-2-ylamino)-phenyl]-2-trifluoromethoxy-benzenesulfonamide.

Using the procedure for the step C of example 2347, the title compoundwas obtained.

ESI MS m/e 584 M+H⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.27 (brs, 1 H), 9.14(brs, 1 H), 7.98 (d, J=8.4 Hz, 1 H), 7.80-7.71 (m, 5 H), 7.60-7.56 (m, 1H), 7.44 (d, J=8.4 Hz, 1 H), 7.15 (t, J=7.4 Hz, 1 H), 6.95 (d, J=16.8Hz, 2 H), 9.29 (s, 6 H).

Example 2349

4′-Chloro-biphenyl-4-carboxylic acid[4-(4-dimethylamino-quinazolin-2-ylamino)-phenyl]-amide trifluoro-aceticacid Synthesis of 4′-chloro-biphenyl-4-carboxylic acid[4-(4-dimethylamino-quinazolin-2-ylamino)-phenyl]-amide trifluoro-aceticacid.

A solution of N²-(4-amino-phenyl)-N⁴,N⁴-dimethyl-quinazoline-2,4-diaminehydrochloride obtained in step B of example 2348 (81.6 mg, 0.258 mmol),4′-chloro-biphenyl-4-carboxylic acid (50.0 mg, 0.215 mmol), HATU (106mg, 0.280 mmol), and diisopropylethylamine (150 μL, 0.860 mmol), inCH₂Cl₂ (2 mL) was stirred at ambient temperature for overnight, and themixture was concentrated. The residue was purifided by HPLC to give4′-chloro-biphenyl-4-carboxylic acid[4-(4-dimethylamino-quinazolin-2-ylamino)-phenyl]-amide trifluoro-aceticacid as a white solid (10 mg, 9%).

ESI MS m/e 494 M+H⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.33 (s, 1 H), 8.17(d, J=8.0 Hz, 1 H), 8.80 (d, J=8.8 Hz, 2 H), 7.85-7.75 (m, 7 H),7.63-7.53 (m, 6 H), 7.36 (t, J=7.6 Hz, 1 H), 3.46 (s, 6 H).

Example 2350

N-[1-(4-Dimethylamino-quinazolin-2-yl)-piperidin-4-ylmethyl]-2-fluoro-benzenesulfonamide

Step A: Synthesis ofN-[1-(4-dimethylamino-quinazolin-2-yl)-piperidin-4-ylmethyl]-2-fluoro-benzenesulfonamide.

To a solution of 4-aminomethyl-piperidine-1-carboxylic acid tert-butylester (60 mg, 0.28 mmol) and diisopropylethylamine (49 mL, 0.28 mmol) inCH₂Cl₂ (2 mL) was added 2-fluorobenzenesulfonyl chloride (54 mg, 0.28mmol) and the mixture was stirred at ambient temperature for 18 hr. Tothe resulting mixture was added trifluoroacetic acid (0.70 mL) andstirred at ambient temperature for 18 hr. The reaction mixture wasconcentrated and neutralized with saturated aqueous NaHCO₃. The aqueouslayer was extracted with EtOAc, and the organic layer was concentratedto give 2-fluoro-N-piperidin-4-ylmethyl-benzenesulfonamide as a paleyellow solid. To a solution of above solid (0.076 g, 0.28 mmol) anddiisopropylethylamine (0.072 mL, 0.42 mmol) in 2-propanol (3 mL) wasadded (2-chloro-quinazolin-4-yl)-dimethyl-amine obtained in step B ofexample 1 (0.044 g, 0.21 mmol) and the resulting mixture was stirred at100° C. for 18 hr. The mixture was concentrated, and the residue waspurified by column chromatography (silica gel, 5% MeOH in CH₂Cl₂) togiveN-[1-(4-dimethylamino-quinazolin-2-yl)-piperidin-4-ylmethyl]-2-fluoro-benzenesulfonamideas a pale yellow solid (0.024 g, 26%).

ESI MS m/e 444 M+H⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 7.98 (m, 1 H), 7.86 (m,1 H), 7.77 (m 1 H), 7.67 (m, 1 H), 7.47-7.29 (m, 4 H), 7.02 (m, 1 H),4.69 (m, 2 H), 3.21 (s, 6 H), 2.76 (m, 4 H), 1.66 (m, 3 H), 1.00 (m, 2H).

Using the procedure for example 2329 and purification by preparativeHPLC, the compounds of example 2351-2819 were obtained.

Using the procedure for example 2331 and purification by preparativeHPLC, the compounds of example 2820-2842 were obtained.

Using the procedure for example 2332, the compounds of example 2843-3003were obtained.

Using the procedure for example 2333, the compounds of example 3004-3090were obtained.

Using the procedure for example 2334, the compounds of example 3091-3161were obtained.

Using the procedure for example 2335 and purification by preparativeHPLC, the compounds of example 3162-3178 were obtained.

Using the procedure for example 2336, the compounds of example 3179-3208were obtained.

Using the procedure for example 2337, the compounds of example 3209 wasobtained.

Using the procedure for example 2338, the compounds of example 3210-3225were obtained.

Using the procedure for example 2339, the compounds of example 3226-3228were obtained.

Using the procedure for example 2340, the compounds of example 3229-3231were obtained.

Using the procedure for example 2341, the compounds of example 3232-3393were obtained.

Using the procedure for example 2342, the compounds of example 3394-3472were obtained.

Using the procedure for example 2343, the compounds of example 3473-3527were obtained.

Using the procedure for example 2346, the compounds of example 3528-3535were obtained.

Using the procedure for example 2347 and purification by preparativeHPLC, the compounds of example 3536-3545 were obtained.

Using the procedure for example 2348 and purification by preparativeHPLC, the compounds of example 3546-3548 were obtained.

Using the procedure for example 2349, the compounds of example 3549-3567were obtained.

Using the procedure for example 2350 and purification by preparativeHPLC, the compounds of example 3568-3579 were obtained.

Retention Example No. Structure ESI-MS Time (min) 2351

454.0 (M + H) 3.60 2352

530.2 (M + H) 4.02 2353

545.4 (M + H) 3.05 2354

496.4 (M + H) 3.49 2355

537.4 (M + H) 3.24 2356

440.0 (M + H) 3.47 2357

484.4 (M + H) 3.49 2358

470.2 (M + H) 3.20 2359

539.4 (M + H) 3.12 2360

522.2 (M + H) 4.22 2361

599.0 (M + H) 3.48 2362

560.2 (M + H) 3.99 2363

584.4 (M + H) 4.06 2364

534.0 (M + H) 3.11 2365

502.4 (M + H) 3.81 2366

530.2 (M + H) 4.04 2367

532.4 (M + H) 3.85 2368

520.2 (M + H) 3.86 2369

474.2 (M + H) 3.72 2370

518.2 (M + H) 3.71 2371

573.2 (M + H) 3.15 2372

556.2 (M + H) 4.38 2373

633.4 (M + H) 3.48 2374

594.2 (M + H) 4.23 2375

582.4 (M + H) 4.26 2376

536.2 (M + H) 4.06 2377

564.2 (M + H) 4.32 2378

566.4 (M + H) 4.11 2379

554.2 (M + H) 4.10 2380

614.2 (M + H) 4.26 2381

524.4 (M + H) 3.87 2382

568.2 (M + H) 3.87 2383

586.2 (M + H) 4.18 2384

614.2 (M + H) 4.45 2385

620.4 (M + H) 4.32 2386

468.2 (M + H) 3.20 2387

551.6 (M + H) 2.82 2388

454.0 (M + H) 3.06 2389

498.6 (M + H) 3.10 2390

484.2 (M + H) 2.76 2391

553.6 (M + H) 2.40 2392

536.4 (M + H) 3.77 2393

613.4 (M + H) 2.74 2394

623.4 (M + H) 3.06 2395

574.4 (M + H) 3.51 2396

562.2 (M + H) 3.59 2397

548.6 (M + H) 2.48 2398

516.4 (M + H) 3.39 2399

550.4 (M + H) 3.56 2400

546.2 (M + H) 3.38 2401

534.0 (M + H) 3.43 2402

608.2 (M + H) 3.75 2403

518 (M + H) 3.22 2404

562.2 (M + H) 3.20 2405

626.0 (M + H) 3.76 2406

614.0 (M + H) 3.72 2407

610.0 (M + H) 3.57 2408

598.2 (M + H) 3.97 2409

564.2 (M + H) 3.46 2410

508.0 (M + H) 3.44 2411

616.2 (M + H) 3.94 2412

604.2 (M + H) 4.51 2413

600.2 (M + H) 4.32 2414

588.0 (M + H) 4.38 2415

650.2 (M + H) 4.20 2416

726.4 (M + H) 4.52 2417

741.6 (M + H) 3.59 2418

692.2 (M + H) 4.12 2419

767.6 (M + H) 4.59 2420

733.4 (M + H) 3.87 2421

636.2 (M + H) 4.08 2422

680.2 (M + H) 4.07 2423

666.0 (M + H) 3.86 2424

735.4 (M + H) 3.50 2425

718.4 (M + H) 4.64 2426

795.6 (M + H) 3.70 2427

744.2 (M + H) 4.43 2428

698.0 (M + H) 4.26 2429

732.4 (M + H) 4.37 2430

726.4 (M + H) 4.52 2431

728.4 (M + H) 4.36 2432

716.4 (M + H) 4.32 2433

616.0 (M + H) 4.22 2434

692.0 (M + H) 4.57 2435

707.2 (M + H) 3.64 2436

658.2 (M + H) 4.15 2437

733.2 (M + H) 4.68 2438

699.2 (M + H) 3.88 2439

646.4 (M + H) 4.08 2440

632.4 (M + H) 3.86 2441

701.4 (M + H) 3.51 2442

684.2 (M + H) 4.75 2443

761.2 (M + H) 3.74 2444

722.2 (M + H) 4.59 2445

710.2 (M + H) 4.60 2446

696.2 (M + H) 3.53 2447

664.2 (M + H) 4.39 2448

692.0 (M + H) 4.65 2449

698.0 (M + H) 4.59 2450

694.2 (M + H) 4.42 2451

682.2 (M + H) 4.42 2452

590.2 (M + H) 4.28 2453

666.2 (M + H) 4.61 2454

681.2 (M + H) 3.72 2455

632.4 (M + H) 4.21 2456

707.2 (M + H) 4.70 2457

673.2 (M + H) 3.94 2458

576.2 (M + H) 4.16 2459

620.4 (M + H) 4.19 2460

606.6 (M + H) 3.94 2461

675.4 (M + H) 3.59 2462

658.6 (M + H) 4.82 2463

735.4 (M + H) 3.82 2464

696.0 (M + H) 4.56 2465

684.4 (M + H) 4.61 2466

670.2 (M + H) 3.56 2467

638.2 (M + H) 4.43 2468

666.2 (M + H) 4.68 2469

672.2 (M + H) 4.60 2470

668.2 (M + H) 4.44 2471

656.4 (M + H) 4.47 2472

585.4 (M + H) 3.32 2473

534.0 (M + H) 3.81 2474

520.4 (M + H) 3.56 2475

589.2 (M + H) 3.25 2476

572.4 (M + H) 4.47 2477

649.4 (M + H) 3.50 2478

610.4 (M + H) 4.26 2479

598.2 (M + H) 4.30 2480

584.4 (M + H) 3.29 2481

552.6 (M + H) 4.11 2482

580.6 (M + H) 4.40 2483

586.2 (M + H) 4.30 2484

582.4 (M + H) 4.14 2485

570.2 (M + H) 4.14 2486

504.2 (M + H) 3.94 2487

580.6 (M + H) 4.34 2488

595.2 (M + H) 3.41 2489

490.2 (M + H) 3.84 2490

534.2 (M + H) 3.84 2491

520.4 (M + H) 3.60 2492

589.2 (M + H) 3.29 2493

572.4 (M + H) 4.51 2494

649.4 (M + H) 3.52 2495

610.2 (M + H) 4.29 2496

598.2 (M + H) 4.34 2497

552.6 (M + H) 4.13 2498

580.6 (M + H) 4.37 2499

586.2 (M + H) 4.30 2500

570.2 (M + H) 4.18 2501

547.4 (M + H) 3.69 2502

623.4 (M + H) 4.10 2503

638.2 (M + H) 3.20 2504

589.2 (M + H) 3.62 2505

664.4 (M + H) 4.25 2506

630.4 (M + H) 3.35 2507

533.2 (M + H) 3.57 2508

577.6 (M + H) 3.58 2509

563.2 (M + H) 3.28 2510

632.6 (M + H) 3.06 2511

615.4 (M + H) 4.30 2512

692.2 (M + H) 3.38 2513

641.4 (M + H) 4.13 2514

595.4 (M + H) 3.89 2515

623.4 (M + H) 4.20 2516

629.2 (M + H) 4.15 2517

613.2 (M + H) 4.02 2518

528.2 (M + H) 4.03 2519

570.2 (M + H) 3.96 2520

611.0 (M + H) 3.69 2521

514.2 (M + H) 3.94 2522

625.4 (M + H) 3.94 2523

558.2 (M + H) 3.96 2524

544.2 (M + H) 3.67 2525

613.2 (M + H) 3.31 2526

596.2 (M + H) 4.69 2527

673.4 (M + H) 3.57 2528

634.4 (M + H) 4.41 2529

622.2 (M + H) 4.45 2530

576 (M + H) 4.25 2531

604.4 (M + H) 4.52 2532

610.2 (M + H) 4.40 2533

606.4 (M + H) 4.29 2534

594.2 (M + H) 4.27 2535

571.8 (M + H) 4.99 2536

609.8 (M + H) 4.43 2537

536.4 (M + H) 4.86 2538

564.6 (M + H) 5.13 2539

530.6 (M + H) 4.65 2540

605.6 (M + H) 5.21 2541

571.6 (M + H) 4.45 2542

568.8 (M + H) 4.09 2543

570.6 (M + H) 5.11 2544

629.6 (M + H) 4.37 2545

655.6 (M + H) 5.35 2546

621.8 (M + H) 4.63 2547

606.8 (M + H) 5.45 2548

644.6 (M + H) 5.21 2549

632.6 (M + H) 5.25 2550

618.6 (M + H) 4.29 2551

616.6 (M + H) 5.14 2552

604.6 (M + H) 5.13 2553

544.6 (M + H) 5.03 2554

585.6 (M + H) 5.13 2555

623.6 (M + H) 4.25 2556

574.6 (M + H) 4.73 2557

649.0 (M + H) 5.25 2558

615.0 (M + H) 4.51 2559

617.4 (M + H) 4.15 2560

600.6 (M + H) 5.37 2561

677.0 (M + H) 4.45 2562

638.6 (M + H) 5.18 2563

612.6 (M + H) 4.16 2564

580.0 (M + H) 5.01 2565

608.0 (M + H) 5.26 2566

613.6 (M + H) 4.44 2567

639.6 (M + H) 5.48 2568

552.6 (M + H) 4.92 2569

607.8 (M + H) 4.33 2570

667.4 (M + H) 4.67 2571

628.6 (M + H) 5.29 2572

602.6 (M + H) 4.35 2573

570.6 (M + H) 5.23 2574

805.4 (M + H) 4.91 2575

730.8 (M + H) 4.47 2576

771.6 (M + H) 4.93 2577

745.6 (M + H) 5.01 2578

580.8 (M + H) 5.18 2579

621.8 (M + H) 5.27 2580

587.6 (M + H) 4.51 2581

584.6 (M + H) 4.21 2582

582.8 (M + H) 5.03 2583

653.8 (M + H) 4.92 2584

604.6 (M + H) 5.33 2585

645.6 (M + H) 5.41 2586

458.6 (M + H) 4.39 2587

458.6 (M + H) 4.40 2588

474.6 (M + H) 4.39 2589

474.6 (M + H) 4.58 2590

542.6 (M + H) 4.79 2591

518.6 (M + H) 4.51 2592

500.8 (M + H) 4.33 2593

524.6 (M + H) 4.61 2594

508.6 (M + H) 4.57 2595

496.8 (M + H) 4.87 2596

446.8 (M + H) 4.29 2597

472.8 (M + H) 4.47 2598

472.8 (M + H) 4.53 2599

488.6 (M + H) 4.55 2600

487.6 (M + H) 4.65 2601

556.6 (M + H) 4.91 2602

523.4 (M + H) 4.61 2603

514.8 (M + H) 4.43 2604

538.6 (M + H) 4.80 2605

510.6 (M + H) 5.00 2606

460.6 (M + H) 4.40 2607

486.6 (M + H) 4.60 2608

484.6 (M + H) 4.64 2609

503.6 (M + H) 4.74 2610

502.6 (M + H) 4.86 2611

570.8 (M + H) 5.00 2612

546.0 (M + H) 4.80 2613

528.8 (M + H) 4.63 2614

552.8 (M + H) 4.90 2615

536.6 (M + H) 4.82 2616

524.8 (M + H) 5.07 2617

474.6 (M + H) 4.55 2618

486.4 (M + H) 4.59 2619

502.6 (M + H) 4.81 2620

552.8 (M + H) 4.94 2621

482.6 (M + H) 4.73 2622

546.6 (M + H) 4.85 2623

536.4 (M + H) 5.08 2624

630.4 (M + H) 5.11 2625

604.6 (M + H) 5.16 2626

518.6 (M + H) 4.75 2627

518.6 (M + H) 4.91 2628

561.6 (M + H) 4.61 2629

500.8 (M + H) 4.75 2630

500.2 (M + H) 4.85 2631

516.6 (M + H) 4.81 2632

516.6 (M + H) 4.95 2633

584.6 (M + H) 5.18 2634

560.6 (M + H) 4.87 2635

542.8 (M + H) 4.80 2636

566.6 (M + H) 5.01 2637

550.8 (M + H) 4.95 2638

538.6 (M + H) 5.20 2639

488.6 (M + H) 4.65 2640

482.6 (M + H) 4.73 2641

516.8 (M + H) 4.97 2642

566.6 (M + H) 5.12 2643

496.8 (M + H) 4.89 2644

560.0 (M + H) 4.98 2645

550.6 (M + H) 5.21 2646

532.6 (M + H) 4.99 2647

532.6 (M + H) 5.03 2648

575.8 (M + H) 4.80 2649

486.6 (M + H) 4.64 2650

486.6 (M + H) 4.66 2651

502.6 (M + H) 4.72 2652

502.6 (M + H) 4.87 2653

570.6 (M + H) 5.03 2654

546.6 (M + H) 4.77 2655

528.8 (M + H) 4.68 2656

552.8 (M + H) 4.89 2657

536.6 (M + H) 4.85 2658

524.8 (M + H) 5.15 2659

474.8 (M + H) 4.63 2660

468.4 (M + H) 4.61 2661

502.6 (M + H) 4.86 2662

546.6 (M + H) 4.64 2663

536.4 (M + H) 4.81 2664

630.4 (M + H) 4.85 2665

604.6 (M + H) 4.87 2666

518.6 (M + H) 4.67 2667

518.6 (M + H) 4.90 2668

561.6 (M + H) 4.64 2669

500.8 (M + H) 4.73 2670

500.8 (M + H) 4.74 2671

516.6 (M + H) 4.89 2672

516.6 (M + H) 4.93 2673

560.0 (M + H) 4.89 2674

542.8 (M + H) 4.76 2675

566.6 (M + H) 5.03 2676

550.8 (M + H) 4.96 2677

538.8 (M + H) 5.25 2678

488.6 (M + H) 4.67 2679

482.4 (M + H) 4.71 2680

516.6 (M + H) 4.95 2681

566.8 (M + H) 5.07 2682

496.8 (M + H) 4.83 2683

560.6 (M + H) 5.01 2684

550.6 (M + H) 5.07 2685

644.6 (M + H) 5.29 2686

618.6 (M + H) 5.25 2687

532.6 (M + H) 5.01 2688

532.6 (M + H) 5.04 2689

575.8 (M + H) 4.75 2690

484.6 (M + H) 4.51 2691

500.8 (M + H) 4.59 2692

500.8 (M + H) 4.71 2693

544.6 (M + H) 4.63 2694

526.8 (M + H) 4.55 2695

550.6 (M + H) 4.79 2696

534.6 (M + H) 4.69 2697

522.4 (M + H) 5.03 2698

472.8 (M + H) 4.43 2699

466.6 (M + H) 4.50 2700

550.6 (M + H) 4.87 2701

480.6 (M + H) 4.65 2702

544.6 (M + H) 4.75 2703

534.6 (M + H) 4.90 2704

628.6 (M + H) 5.08 2705

602.6 (M + H) 5.10 2706

516.8 (M + H) 4.71 2707

516.8 (M + H) 4.81 2708

559.6 (M + H) 4.50 2709

498.8 (M + H) 4.64 2710

498.8 (M + H) 4.73 2711

514.8 (M + H) 4.87 2712

564.6 (M + H) 4.93 2713

548.6 (M + H) 4.87 2714

536.6 (M + H) 5.19 2715

603.8 (M + H) 4.76 2716

603.4 (M + H) 4.87 2717

671.6 (M + H) 5.05 2718

647.6 (M + H) 4.79 2719

629.8 (M + H) 4.67 2720

653.8 (M + H) 4.91 2721

637.8 (M + H) 4.85 2722

625.8 (M + H) 5.14 2723

575.6 (M + H) 4.63 2724

569.8 (M + H) 4.66 2725

603.8 (M + H) 4.88 2726

653.8 (M + H) 5.01 2727

583.8 (M + H) 4.77 2728

647 (M + H) 4.92 2729

637.8 (M + H) 5.13 2730

731.6 (M + H) 5.19 2731

705.8 (M + H) 5.22 2732

619.8 (M + H) 4.91 2733

619.8 (M + H) 4.93 2734

663.0 (M + H) 4.67 2735

631.8 (M + H) 5.01 2736

699.0 (M + H) 5.19 2737

675.8 (M + H) 4.95 2738

657.8 (M + H) 4.81 2739

665.8 (M + H) 4.97 2740

653.8 (M + H) 5.27 2741

603.4 (M + H) 4.77 2742

597.8 (M + H) 4.79 2743

631.8 (M + H) 5.02 2744

681.8 (M + H) 5.14 2745

611.8 (M + H) 4.93 2746

675.0 (M + H) 5.05 2747

655.8 (M + H) 5.29 2748

759.6 (M + H) 5.31 2749

733.8 (M + H) 5.36 2750

647.8 (M + H) 5.05 2751

647.8 (M + H) 5.08 2752

691.0 (M + H) 4.89 2753

559.6 (M + H) 4.51 2754

575.6 (M + H) 4.57 2755

575.6 (M + H) 4.69 2756

619.6 (M + H) 4.63 2757

625.8 (M + H) 4.72 2758

609.8 (M + H) 4.67 2759

514.8 (M + H) 4.45 2760

625.8 (M + H) 4.38 2761

555.8 (M + H) 4.57 2762

609.8 (M + H) 4.94 2763

677.8 (M + H) 5.05 2764

591.6 (M + H) 4.73 2765

591.6 (M + H) 4.75 2766

635.0 (M + H) 4.47 2767

503.6 (M + H) 3.83 2768

503.6 (M + H) 3.99 2769

571.6 (M + H) 4.16 2770

547.6 (M + H) 3.85 2771

529.6 (M + H) 3.75 2772

553.8 (M + H) 3.99 2773

537.6 (M + H) 3.93 2774

525.8 (M + H) 4.22 2775

475.6 (M + H) 3.64 2776

469.6 (M + H) 3.71 2777

503.6 (M + H) 3.97 2778

553.8 (M + H) 4.17 2779

483.4 (M + H) 3.87 2780

547.6 (M + H) 4.04 2781

537.4 (M + H) 4.23 2782

631.6 (M + H) 4.23 2783

605.8 (M + H) 4.41 2784

519.6 (M + H) 4.01 2785

519.6 (M + H) 4.07 2786

562.6 (M + H) 3.77 2787

531.6 (M + H) 3.90 2788

531.6 (M + H) 4.04 2789

599.6 (M + H) 4.24 2790

575.0 (M + H) 3.95 2791

557.6 (M + H) 3.86 2792

565.6 (M + H) 4.03 2793

554 (M + H) 4.29 2794

503.6 (M + H) 3.78 2795

497.6 (M + H) 3.83 2796

531.6 (M + H) 4.05 2797

582.0 (M + H) 4.23 2798

511 (M + H) 3.95 2799

575.6 (M + H) 4.10 2800

565.0 (M + H) 4.32 2801

659.6 (M + H) 4.35 2802

634.0 (M + H) 4.43 2803

547.6 (M + H) 4.09 2804

547.6 (M + H) 4.15 2805

590.6 (M + H) 3.93 2806

495.6 (M + H) 4.07 2807

477.6 (M + H) 4.07 2808

475.6 (M + H) 4.07 2809

475.6 (M + H) 4.23 2810

501.8 (M + H) 4.15 2811

509.4 (M + H) 4.27 2812

525.6 (M + H) 4.37 2813

519.6 (M + H) 4.25 2814

509.4 (M + H) 4.49 2815

603.0 (M + H) 4.60 2816

577.6 (M + H) 4.72 2817

491 (M + H) 4.31 2818

491.6 (M + H) 4.33 2819

534.6 (M + H) 4.01 2820

325.4 (M + H) 3.91 2821

359.4 (M + H) 4.24 2822

409.4 (M + H) 4.51 2823

339.6 (M + H) 4.09 2824

403.4 (M + H) 4.28 2825

393.0 (M + H) 4.57 2826

521.6 (M + H) 4.69 2827

491.6 (M + H) 4.77 2828

375.4 (M + H) 4.33 2829

375.4 (M + H) 4.39 2830

418.8 (M + H) 4.33 2831

343.4 (M + H) 3.96 2832

343.4 (M + H) 4.03 2833

359.4 (M + H) 4.05 2834

359.4 (M + H) 4.24 2835

403.4 (M + H) 4.07 2836

385.4 (M + H) 4.00 2837

409.4 (M + H) 4.32 2838

393.6 (M + H) 4.23 2839

381.6 (M + H) 4.62 2840

330.8 (M + H) 3.83 2841

361.4 (M + H) 4.05 2842

427.4 (M + H) 4.51 2843

458.4 (M + H) 3.22 2844

415.4 (M + H) 3.01 2845

432.6 (M + H) 3.26 2846

396.2 (M + H) 2.81 2847

450.0 (M + H) 3.09 2848

408.4 (M + H) 2.85 2849

434.4 (M + H) 2.89 2850

440.0 (M + H) 3.20 2851

482.4 (M + H) 3.43 2852

466.4 (M + H) 2.71 2853

380.2 (M + H) 2.72 2854

429.2 (M + H) 2.91 2855

450.0 (M + H) 2.82 2856

434.4 (M + H) 2.69 2857

440.0 (M + H) 2.85 2858

550.6 (M + H) 3.80 2859

441.4 (M + H) 3.03 2860

446.6 (M + H) 3.41 2861

448.4 (M + H) 2.91 2862

424.2 (M + H) 3.05 2863

441.4 (M + H) 2.68 2864

463.4 (M + H) 2.76 2865

408.4 (M + H) 2.91 2866

492.2 (M + H) 3.30 2867

464.2 (M + H) 2.93 2868

474.4 (M + H) 3.27 2869

390.6 (M + H) 2.88 2870

482.2 (M + H) 3.43 2871

408.4 (M + H) 2.91 2872

420.4 (M + H) 2.91 2873

468.2 (M + H) 3.09 2874

406.4 (M + H) 2.80 2875

464.2 (M + H) 2.97 2876

524.6 (M + H) 3.12 2877

442.4 (M + H) 3.10 2878

426.2 (M + H) 2.90 2879

480.2 (M + H) 2.89 2880

468.2 (M + H) 3.07 2881

422.4 (M + H) 2.61 2882

450.0 (M + H) 2.93 2883

404.6 (M + H) 3.01 2884

436.4 (M + H) 3.08 2885

440.0 (M + H) 3.18 2886

470.4 (M + H) 3.25 2887

450.0 (M + H) 3.01 2888

466.4 (M + H) 3.40 2889

415.4 (M + H) 2.83 2890

458.4 (M + H) 3.25 2891

468.2 (M + H) 3.00 2892

406.4 (M + H) 2.66 2893

420.4 (M + H) 2.92 2894

379.4 (M + H) 2.71 2895

434.4 (M + H) 2.87 2896

480.2 (M + H)\ 3.17 2897

426.2 (M + H) 2.98 2898

480.2 (M + H) 2.99 2899

528.4 (M + H) 3.15 2900

458.4 (M + H) 3.19 2901

480.2 (M + H) 2.92 2902

470.4 (M + H) 3.27 2903

404.6 (M + H) 2.87 2904

460.4 (M + H) 3.48 2905

410.4 (M + H) 2.96 2906

450.0 (M + H) 3.03 2907

434.4 (M + H) 3.08 2908

452.2 (M + H) 2.79 2909

396.2 (M + H) 2.81 2910

459.4 (M + H) 3.21 2911

458.2 (M + H) 3.08 2912

410.4 (M + H) 2.88 2913

426.2 (M + H) 3.01 2914

429.4 (M + H) 2.97 2915

507.2 (M + H) 3.53 2916

522.4 (M + H) 3.56 2917

483.2 (M + H) 2.80 2918

507.2 (M + H) 3.27 2919

474.2 (M + H) 3.10 2920

450.0 (M + H) 3.00 2921

498.4 (M + H) 3.15 2922

459.4 (M + H) 2.99 2923

476.0 (M + H) 3.10 2924

518.2 (M + H) 3.10 2925

476.2 (M + H) 3.12 2926

490.4 (M + H) 3.35 2927

434.4 (M + H) 3.11 2928

478.4 (M + H) 3.29 2929

438.2 (M + H) 3.01 2930

433.4 (M + H) 2.59 2931

438.2 (M + H) 2.90 2932

456.2 (M + H) 3.10 2933

492.2 (M + H) 3.25 2934

476.2 (M + H) 3.11 2935

490.4 (M + H) 3.20 2936

448.4 (M + H) 3.17 2937

489.6 (M + H) 3.31 2938

528.2 (M + H) 3.03 2939

476.2 (M + H) 2.99 2940

447.4 (M + H) 2.66 2941

532.4 (M + H) 3.66 2942

514.4 (M + H) 3.08 2943

393.4 (M + H) 2.79 2944

474.4 (M + H) 3.24 2945

526.6 (M + H) 3.44 2946

526.6 (M + H) 3.42 2947

490.4 (M + H) 3.35 2948

462.2 (M + H) 3.43 2949

418.6 (M + H) 3.13 2950

458.4 (M + H) 3.10 2951

476.4 (M + H) 3.19 2952

438.2 (M + H) 2.95 2953

422.4 (M + H) 2.61 2954

458.2 (M + H) 3.07 2955

470.4 (M + H) 3.45 2956

471.6 (M + H) 2.88 2957

472.4 (M + H) 3.36 2958

450 (M + H) 2.75 2959

448.4 (M + H) 3.20 2960

508.4 (M + H) 3.00 2961

420.4 (M + H) 2.80 2962

474.4 (M + H) 3.20 2963

404.4 (M + H) 2.87 2964

458.2 (M + H) 3.00 2965

394.4 (M + H) 2.30 2966

505.4 (M + H) 2.60 2967

424.2 (M + H) 3.00 2968

436.4 (M + H) 2.71 2969

432.4 (M + H) 3.30 2970

424.2 (M + H) 2.95 2971

415.4 (M + H) 2.79 2972

480.2 (M + H) 3.00 2973

496.2 (M + H) 3.46 2974

562.2 (M + H) 2.99 2975

492.4 (M + H) 3.64 2976

492.2 (M + H) 3.25 2977

448.4 (M + H) 3.22 2978

456.2 (M + H) 3.09 2979

434.4 (M + H) 2.89 2980

436.4 (M + H) 2.79 2981

438.2 (M + H) 2.91 2982

441.4 (M + H) 2.55 2983

446.4 (M + H) 3.13 2984

461.4 (M + H) 2.46 2985

422.2 (M + H) 3.01 2986

510.2 (M + H) 2.85 2987

414.4 (M + H) 2.86 2988

534.2 (M + H) 3.13 2989

424.2 (M + H) 3.08 2990

510.4 (M + H) 3.32 2991

510.4 (M + H) 3.17 2992

476.4 (M + H) 3.17 2993

476.2 (M + H) 3.21 2994

454.2 (M + H) 2.77 2995

468.4 (M + H) 2.89 2996

418.6 (M + H) 3.12 2997

496.4 (M + H) 3.29 2998

472.6 (M + H) 2.99 2999

466.4 (M + H) 3.37 3000

574.2 (M + H) 3.64 3001

430.4 (M + H) 3.05 3002

532.4 (M + H) 4.05 3003

552.0 (M + H) 3.37 3004

448.4 (M + H) 3.51 3005

454.2 (M + H) 3.91 3006

472.4 (M + H) 4.02 3007

494.4 (M + H) 4.01 3008

537.4 (M + H) 3.77 3009

418.6 (M + H) 3.63 3010

418.6 (M + H) 3.51 3011

396.2 (M + H) 3.47 3012

434.4 (M + H) 3.52 3013

395.4 (M + H) 3.15 3014

460.2 (M + H) 4.03 3015

418.6 (M + H) 3.65 3016

462.2 (M + H) 4.09 3017

482.2 (M + H) 3.79 3018

498.6 (M + H) 3.88 3019

483.2 (M + H) 3.80 3020

478.2 (M + H) 3.49 3021

450.0 (M + H) 3.61 3022

448.2 (M + H) 3.70 3023

554.4 (M + H) 4.41 3024

598.2 (M + H) 4.03 3025

499.2 (M + H) 3.59 3026

524.6 (M + H) 3.84 3027

497.4 (M + H) 3.80 3028

410.2 (M + H) 3.43 3029

468.2 (M + H) 3.77 3030

463.2 (M + H) 3.73 3031

490.4 (M + H) 3.91 3032

490.4 (M + H) 3.94 3033

490.4 (M + H) 3.85 3034

490.4 (M + H) 3.87 3035

490.4 (M + H) 3.63 3036

490.2 (M + H) 3.54 3037

540.4 (M + H) 3.95 3038

440.4 (M + H) 3.58 3039

458.4 (M + H) 3.56 3040

476.4 (M + H) 3.83 3041

490.4 (M + H) 3.82 3042

508.0 (M + H) 3.85 3043

438.2 (M + H) 3.71 3044

464.2 (M + H) 3.65 3045

448.4 (M + H) 3.47 3046

440.4 (M + H) 3.59 3047

464.2 (M + H) 3.36 3048

464.4 (M + H) 3.39 3049

432.4 (M + H) 3.81 3050

448.4 (M + H) 3.69 3051

438.2 (M + H) 3.69 3052

472.4 (M + H) 4.03 3053

429.2 (M + H) 3.47 3054

488.4 (M + H) 4.60 3055

424.2 (M + H) 3.41 3056

530.2 (M + H) 3.83 3057

446.4 (M + H) 4.02 3058

438.2 (M + H) 3.70 3059

472.4 (M + H) 3.55 3060

506.4 (M + H) 3.71 3061

530.2 (M + H) 3.61 3062

474.4 (M + H) 4.41 3063

476.4 (M + H) 4.14 3064

502.4 (M + H) 4.83 3065

480.4 (M + H) 4.09 3066

486.4 (M + H) 3.84 3067

440.4 (M + H) 3.46 3068

494.4 (M + H) 3.79 3069

472.4 (M + H) 3.55 3070

464.4 (M + H) 3.63 3071

458.2 (M + H) 3.69 3072

440.4 (M + H) 3.69 3073

440.4 (M + H) 3.66 3074

422.4 (M + H) 3.55 3075

460.4 (M + H) 4.24 3076

429.2 (M + H) 3.42 3077

434.4 (M + H) 3.61 3078

488.4 (M + H) 3.86 3079

518.6 (M + H) 4.74 3080

458.2 (M + H) 3.68 3081

410.4 (M + H) 3.58 3082

540.4 (M + H) 4.19 3083

422.2 (M + H) 3.50 3084

494.4 (M + H) 3.39 3085

440.0 (M + H) 3.55 3086

438.2 (M + H) 3.48 3087

454.2 (M + H) 3.75 3088

472.4 (M + H) 3.83 3089

422.2 (M + H) 3.51 3090

472.4 (M + H) 3.87 3091

500.4 (M + H) 3.03 3092

447.4 (M + H) 2.59 3093

486.4 (M + H) 3.25 3094

488.4 (M + H) 2.81 3095

452.4 (M + H) 2.98 3096

496.4 (M + H) 3.29 3097

448.4 (M + H) 2.77 3098

458.4 (M + H) 3.06 3099

484.4 (M + H) 3.40 3100

418.6 (M + H) 2.69 3101

496.6 (M + H) 3.01 3102

483.4 (M + H) 2.79 3103

420.4 (M + H) 2.76 3104

516.2 (M + H) 3.03 3105

480.4 (M + H) 2.41 3106

483.2 (M + H) 2.84 3107

455 (M + H) 2.45 3108

455.2 (M + H) 3.19 3109

461.4 (M + H) 2.60 3110

447.4 (M + H) 2.74 3111

466.6 (M + H) 2.61 3112

464.4 (M + H) 2.35 3113

468.4 (M + H) 3.04 3114

456.2 (M + H) 2.44 3115

455.2 (M + H) 2.11 3116

454.2 (M + H) 3.21 3117

433.6 (M + H) 2.34 3118

444.6 (M + H) 2.93 3119

421.4 (M + H) 2.23 3120

506.4 (M + H) 3.31 3121

511.6 (M + H) 3.21 3122

479.4 (M + H) 3.60 3123

434.4 (M + H) 2.37 3124

516.4 (M + H) 3.02 3125

394.4 (M + H) 2.45 3126

450.2 (M + H) 2.41 3127

477.0 (M + H) 2.88 3128

405.6 (M + H) 2.61 3129

472.6 (M + H) 3.17 3130

464.4 (M + H) 2.59 3131

484.2 (M + H) 2.99 3132

453.0 (M + H) 2.45 3133

488.4 (M + H) 3.59 3134

454.2 (M + H) 2.81 3135

421.4 (M + H) 2.89 3136

468.4 (M + H) 2.53 3137

483.2 (M + H) 2.83 3138

487.4 (M + 2H+) 3.40 3139

445.6 (M + H) 2.36 3140

453.2 (M + H) 2.46 3141

478.4 (M + H) 2.77 3142

672.2 (M + H) 3.92 3143

576.2 (M + H) 3.71 3144

421.2 (M + H) 2.01 3145

494.4 (M + H) 2.77 3146

405.6 (M + H) 1.99 3147

488.4 (M + H) 3.13 3148

430.4 (M + H) 2.91 3149

459.4 (M + H) 2.47 3150

486.6 (M + H) 2.93 3151

474.4 (M + H) 3.03 3152

464.2 (M + H) 3.13 3153

483.4 (M + H) 2.67 3154

556.4 (M + H) 2.84 3155

443.4 (M + H) 2.94 3156

508.2 (M + H) 3.20 3157

440.0 (M + H) 2.72 3158

532.4 (M + H) 3.58 3159

535.4 (M + H) 3.51 3160

504.4 (M + H) 3.49 3161

572.4 (M + H) 3.71 3162

460.2 (M + H) 3.80 3163

589.2 (M + H) 4.00 3164

492.2 (M + H) 3.90 3165

478.2 (M + H) 3.80 3166

607.6 (M + H) 4.00 3167

504.2 (M + H) 3.40 3168

506.2 (M + H) 3.90 3169

480.2 (M + H) 3.80 3170

466.2 (M + H) 3.70 3171

515.2 (M + H) 3.90 3172

644.2 (M + H) 4.10 3173

488.2 (M + H) 3.90 3174

474.4 (M + H) 3.80 3175

525.4 (M + H) 3.70 3176

654.2 (M + H) 3.90 3177

428.2 (M + H) 3.10 3178

414.4 (M + H) 2.90 3179

506.4 (M + H) 3.04 3180

578.8 (M + H) 3.50 3181

520.6 (M + H) 3.19 3182

448.4 (M + H) 2.80 3183

494.6 (M + H) 2.66 3184

478.4 (M + H) 2.66 3185

492.6 (M + H) 2.94 3186

464.4 (M + H) 2.65 3187

464.4 (M + H) 2.68 3188

566.4 (M + H) 3.03 3189

512.6 (M + H) 2.85 3190

474.4 (M + H) 3.09 3191

477.4 (M + H) 2.51 3192

464.4 (M + H) 2.67 3193

494.6 (M + H) 2.78 3194

494.6 (M + H) 2.60 3195

434.6 (M + H) 2.67 3196

546.4 (M + H) 4.30 3197

606.6 (M + H) 3.95 3198

536.6 (M + H) 3.83 3199

492.4 (M + H) 2.97 3200

478.4 (M + H) 2.79 3201

542.0 (M + H) 2.85 3202

492.6 (M + H) 2.81 3203

590.4 (M + H) 3.02 3204

502.2 (M + H) 2.91 3205

480.4 (M + H) 2.51 3206

536.4 (M + H) 3.21 3207

443.6 (M + H) 2.66 3208

536.4 (M + H) 3.08 3209

520.0 (M + H) 3.51 3210

480.4 (M + H) 2.58 3211

552.0 (M + H) 3.11 3212

464.4 (M + H) 3.22 3213

450.4 (M + H) 2.70 3214

450.4 (M + H) 2.58 3215

480.4 (M + H) 2.73 3216

429.4 (M + H) 3.29 3217

480.2 (M + H) 2.78 3218

522.4 (M + H) 3.77 3219

450.2 (M + H) 2.57 3220

480.0 (M + H) 2.97 3221

478.4 (M + H) 3.17 3222

480.0 (M + H) 3.08 3223

590.2 (M + H) 4.20 3224

576.4 (M + H) 3.95 3225

512.4 (M + H) 3.86 3226

472.4 (M + H) 3.07 3227

540.6 (M + H) 3.75 3228

464.4 (M + H) 3.07 3229

478.4 (M + H) 3.40 3230

552.6 (M + H) 3.50 3231

590.2 (M + H) 3.60 3232

418.6 (M + H) 3.25 3233

382.2 (M + H) 2.67 3234

436.4 (M + H) 3.05 3235

394.4 (M + H) 2.75 3236

420.4 (M + H) 2.82 3237

426.4 (M + H) 3.17 3238

468.4 (M + H) 3.44 3239

452.2 (M + H) 2.69 3240

436.4 (M + H) 2.80 3241

426.2 (M + H) 2.79 3242

536.4 (M + H) 3.75 3243

427.2 (M + H) 2.95 3244

432.4 (M + H) 3.41 3245

434.2 (M + H) 2.84 3246

410.2 (M + H) 3.02 3247

427.4 (M + H) 2.61 3248

450.4 (M + H) 2.91 3249

460.4 (M + H) 3.19 3250

468.4 (M + H) 2.79 3251

394.4 (M + H) 2.83 3252

454.2 (M + H) 3.08 3253

392.4 (M + H) 2.73 3254

450.4 (M + H) 2.92 3255

510.4 (M + H) 3.17 3256

428.2 (M + H) 3.08 3257

392.4 (M + H) 2.63 3258

412.2 (M + H) 2.83 3259

466.4 (M + H) 2.89 3260

454.0 (M + H) 3.05 3261

408.2 (M + H) 2.53 3262

390.4 (M + H) 2.92 3263

422.2 (M + H) 3.05 3264

456.4 (M + H) 3.25 3265

452.2 (M + H) 3.37 3266

401.2 (M + H) 2.76 3267

444.4 (M + H) 3.17 3268

392.4 (M + H) 2.61 3269

406.4 (M + H) 2.86 3270

365.4 (M + H) 2.61 3271

420.4 (M + H) 2.83 3272

466.4 (M + H) 3.10 3273

514.4 (M + H) 3.13 3274

444.4 (M + H) 3.17 3275

466.4 (M + H) 2.86 3276

456.2 (M + H) 3.22 3277

446.6 (M + H) 3.45 3278

436.4 (M + H) 2.95 3279

420.2 (M + H) 3.03 3280

382.4 (M + H) 2.72 3281

444.4 (M + H) 3.07 3282

396.2 (M + H) 2.79 3283

412.4 (M + H) 2.95 3284

493.4 (M + H) 3.57 3285

508.2 (M + H) 3.52 3286

469.6 (M + H) 2.76 3287

493.2 (M + H) 3.17 3288

460.2 (M + H) 2.95 3289

484.2 (M + H) 3.14 3290

462.2 (M + H) 3.11 3291

462.2 (M + H) 3.11 3292

476.4 (M + H) 3.39 3293

420.4 (M + H) 3.05 3294

464.2 (M + H) 3.21 3295

424.2 (M + H) 2.94 3296

419.4 (M + H) 2.51 3297

366.4 (M + H) 2.26 3298

424.2 (M + H) 2.93 3299

442.4 (M + H) 2.97 3300

478.2 (M + H) 3.19 3301

462.2 (M + H) 3.05 3302

476.4 (M + H) 3.20 3303

366.4 (M + H) 2.64 3304

412.4 (M + H) 2.85 3305

420.4 (M + H) 2.67 3306

449.4 (M + H) 2.74 3307

394.4 (M + H) 2.86 3308

478.2 (M + H) 3.38 3309

444.4 (M + H) 3.09 3310

376.4 (M + H) 2.82 3311

406.4 (M + H) 2.87 3312

436.4 (M + H) 2.91 3313

426.2 (M + H) 3.13 3314

436.4 (M + H) 2.99 3315

454.0 (M + H) 2.97 3316

412.4 (M + H) 2.92 3317

466.4 (M + H) 2.95 3318

390.4 (M + H) 2.95 3319

396.2 (M + H) 2.89 3320

438.2 (M + H) 2.76 3321

445.4 (M + H) 3.16 3322

415.4 (M + H) 2.96 3323

445.4 (M + H) 2.96 3324

504.2 (M + H) 3.11 3325

434.4 (M + H) 3.17 3326

476.2 (M + H) 3.27 3327

514.4 (M + H) 3.07 3328

462.2 (M + H) 2.99 3329

433.2 (M + H) 2.63 3330

518.4 (M + H) 3.63 3331

500.4 (M + H) 3.09 3332

379.4 (M + H) 2.77 3333

460.2 (M + H) 3.31 3334

512.4 (M + H) 3.51 3335

512.6 (M + H) 3.51 3336

476.2 (M + H) 3.39 3337

448.4 (M + H) 3.42 3338

404.4 (M + H) 3.17 3339

444.4 (M + H) 3.13 3340

462.2 (M + H) 3.21 3341

424.2 (M + H) 2.97 3342

444.6 (M + H) 3.16 3343

469.4 (M + H) 3.47 3344

456.4 (M + H) 3.47 3345

457.4 (M + H) 3.09 3346

458.2 (M + H) 3.37 3347

436.4 (M + H) 2.83 3348

434.4 (M + H) 3.30 3349

494.4 (M + H) 2.98 3350

406.4 (M + H) 2.80 3351

460.4 (M + H) 3.20 3352

390.4 (M + H) 2.97 3353

444.2 (M + H) 3.01 3354

380.2 (M + H) 2.27 3355

491.4 (M + H) 2.55 3356

410.4 (M + H) 3.05 3357

422.2 (M + H) 2.69 3358

418.6 (M + H) 3.36 3359

410.4 (M + H) 2.97 3360

401.2 (M + H) 2.81 3361

466.2 (M + H) 3.01 3362

482.4 (M + H) 3.43 3363

548.4 (M + H) 3.03 3364

543.6 (M + H) 3.95 3365

478.4 (M + H) 3.64 3366

478.4 (M + H) 3.29 3367

434.4 (M + H) 3.20 3368

442.4 (M + H) 3.09 3369

420.4 (M + H) 2.87 3370

422.2 (M + H) 2.79 3371

424.2 (M + H) 2.96 3372

427.2 (M + H) 2.53 3373

432.4 (M + H) 3.12 3374

447.4 (M + H) 2.45 3375

408.2 (M + H) 3.02 3376

496.4 (M + H) 2.81 3377

400.2 (M + H) 2.81 3378

520.2 (M + H) 3.14 3379

410.4 (M + H) 3.12 3380

496.4 (M + H) 3.40 3381

496.4 (M + H) 3.17 3382

462.2 (M + H) 3.19 3383

462.2 (M + H) 3.28 3384

440.4 (M + H) 2.74 3385

454.2 (M + H) 2.89 3386

404.4 (M + H) 3.09 3387

482.2 (M + H) 3.29 3388

458.4 (M + H) 2.99 3389

452.2 (M + H) 3.40 3390

560.2 (M + H) 3.73 3391

416.4 (M + H) 2.99 3392

518.6 (M + H) 4.08 3393

436.4 (M + H) 2.95 3394

434.4 (M + H) 3.30 3395

440.4 (M + H) 4.26 3396

458.2 (M + H) 4.39 3397

480.4 (M + H) 4.37 3398

523.6 (M + H) 4.15 3399

404.4 (M + H) 3.46 3400

404.4 (M + H) 3.75 3401

382.4 (M + H) 3.65 3402

420.4 (M + H) 3.81 3403

381.2 (M + H) 3.33 3404

404.4 (M + H) 3.93 3405

435.2 (M + H) 3.40 3406

484.4 (M + H) 4.15 3407

469.4 (M + H) 4.20 3408

436.2 (M + H) 3.88 3409

434.4 (M + H) 3.91 3410

558.4 (M + H) 4.92 3411

483.4 (M + H) 4.08 3412

396.2 (M + H) 3.68 3413

454.2 (M + H) 3.70 3414

449.4 (M + H) 4.09 3415

476.2 (M + H) 4.33 3416

476.4 (M + H) 3.60 3417

476.4 (M + H) 4.23 3418

476.4 (M + H) 4.38 3419

426.2 (M + H) 3.87 3420

444.4 (M + H) 3.86 3421

462.2 (M + H) 4.15 3422

424.2 (M + H) 4.06 3423

450.4 (M + H) 4.03 3424

434.2 (M + H) 3.75 3425

426.2 (M + H) 3.88 3426

450.4 (M + H) 3.64 3427

450.4 (M + H) 3.55 3428

418.6 (M + H) 4.17 3429

404.4 (M + H) 4.03 3430

458.2 (M + H) 4.45 3431

415.4 (M + H) 3.76 3432

474.4 (M + H) 5.06 3433

410.2 (M + H) 3.64 3434

516.2 (M + H) 4.24 3435

424.2 (M + H) 4.09 3436

458.2 (M + H) 3.89 3437

516.2 (M + H) 3.88 3438

460.4 (M + H) 4.86 3439

488.4 (M + H) 4.70 3440

472.4 (M + H) 4.29 3441

426.2 (M + H) 3.69 3442

480.2 (M + H) 4.16 3443

458.2 (M + H) 3.91 3444

450.4 (M + H) 3.95 3445

444.4 (M + H) 4.01 3446

426.2 (M + H) 4.00 3447

408.4 (M + H) 3.75 3448

446.6 (M + H) 4.65 3449

415.2 (M + H) 3.75 3450

420.4 (M + H) 3.91 3451

490.4 (M + H) 4.99 3452

504.4 (M + H) 5.16 3453

444.4 (M + H) 4.00 3454

396.2 (M + H) 3.85 3455

526.6 (M + H) 4.69 3456

408.4 (M + H) 3.30 3457

480.4 (M + H) 3.76 3458

426.2 (M + H) 3.86 3459

424.2 (M + H) 3.76 3460

440.4 (M + H) 4.05 3461

458.4 (M + H) 4.25 3462

408.2 (M + H) 3.84 3463

458.2 (M + H) 4.25 3464

446.6 (M + H) 4.44 3465

470.2 (M + H) 4.13 3466

479.2 (M + H) 4.25 3467

476.2 (M + H) 3.92 3468

526.4 (M + H) 4.31 3469

476.2 (M + H) 4.15 3470

462.2 (M + H) 4.48 3471

466.4 (M + H) 4.45 3472

474.4 (M + H) 4.29 3473

486.2 (M + H) 4.32 3474

438.4 (M + H) 4.32 3475

441.4 (M + H) 3.75 3476

434.4 (M + H) 4.10 3477

469.4 (M + H) 4.19 3478

444.4 (M + H) 4.36 3479

482.4 (M + H) 4.35 3480

482.4 (M + H) 4.64 3481

502.2 (M + H) 4.37 3482

458.2 (M + H) 4.08 3483

465.4 (M + H) 3.66 3484

404.4 (M + H) 4.03 3485

469.4 (M + H) 4.23 3486

447.4 (M + H) 3.94 3487

456.2 (M + H) 4.07 3488

432.4 (M + H) 3.99 3489

441.3 (M + H) 1.70 3490

440.2 (M + H) 4.57 3491

393.4 (M + H) 4.01 3492

497.4 (M + H) 4.45 3493

470.2 (M + H) 2.40 3494

439.4 (M + H) 1.92 3495

407.4 (M + H) 2.30 3496

469.5 (M + H) 2.27 3497

439.4 (M + H) 1.93 3498

407.4 (M + H) 1.62 3499

416.3 (M + H) 2.34 3500

460.4 (M + H) 2.46 3501

465.4 (M + H) 4.13 3502

419.4 (M + H) 3.87 3503

450.4 (M + H) 3.97 3504

406.2 (M + H) 2.18 3505

470.4 (M + H) 4.74 3506

466.4 (M + H) 3.83 3507

441.2 (M + H) 4.38 3508

441.2 (M + H) 3.62 3509

454.5 (M + H) 2.44 3510

384.4 (M + H) 3.67 3511

502.2 (M + H) 4.37 3512

480.5 (M + H) 2.18 3513

380.2 (M + H) 3.81 3514

463.2 (M + H) 4.23 3515

443.4 (M + H) 2.12 3516

431.1 (M + H) 1.90 3517

474.4 (M + H) 5.05 3518

440.5 (M + H) 2.33 3519

440.5 (M + H) 2.33 3520

391.1 (M + H) 1.59 3521

474.4 (M + H) 4.53 3522

429.3 (M + H) 2.41 3523

429.3 (M + H) 2.41 3524

494.6 (M + H) 2.59 3525

518.5 (M + H) 2.96 3526

420.4 (M + H) 2.19 3527

420.4 (M + H) 2.19 3528

552.0 (M + H) 2.45 3529

564.2 (M + H) 2.48 3530

606.0 (M + H) 2.86 3531

586.2 (M + H) 3.20 3532

614.4 (M + H) 2.76 3533

620.0 (M + H) 2.68 3534

616.0 (M + H) 2.56 3535

566.0 (M + H) 2.54 3536

532.2 (M + H) 3.35 3537

514.4 (M + H) 3.11 3538

505.2 (M + H) 2.98 3539

556 (M + H) 3.37 3540

516.4 (M + H) 3.39 3541

504.4 (M + H) 3.61 3542

574.4 (M + H) 4.27 3543

508.2 (M + H) 3.17 3544

644.2 (M + H) 3.63 3545

520.4 (M + H) 3.56 3546

504.2 (M + H) 3.25 3547

513.4 (M + H) 2.86 3548

616.2 (M + H) 3.73 3549

450.4 (M + H) 2.79 3550

466.2 (M + H) 3.35 3551

465.2 (M + H) 3.34 3552

451.4 (M + H) 3.83 3553

451.2 (M + H) 4.10 3554

563.2 (M + H) 4.33 3555

468.4 (M + H) 3.66 3556

467.4 (M + H) 2.85 3557

515.4 (M + H) 3.52 3558

485.2 (M + H) 3.40 3559

467.4 (M + H) 3.90 3560

473.4 (M + H) 4.17 3561

467.4 (M + H) 3.57 3562

490.2 (M + H) 4.00 3563

490.2 (M + H) 3.99 3564

476.2 (M + H) 3.76 3565

467.2 (M + H) 4.07 3566

528.2 (M + H) 4.53 3567

464.2 (M + H) 4.11 3568

494.0 (M + H) 3.43 3564

444.0 (M + H) 3.03 3570

552.0 (M + H) 3.30 3571

510.0 (M + H) 3.37 3572

562.0 (M + H) 3.66 3573

622.0 (M + H) 3.61 3574

588.0 (M + H) 3.59 3575

510.0 (M + H) 3.31 3576

562.0 (M + H) 3.61 3577

510.0 (M + H) 3.35 3578

597.0 (M + H) 3.55 3579

665.0 (M + H) 4.02Assay Procedures

Compounds identified and disclosed throughout this patent document wereassayed according to the protocols found in co-pending patentapplication having U.S. Ser. No. 09/826,509, which is incorporatedherein by reference.

Example 3580 Preparation of Endogenous MCH Receptor

The endogenous human MCH receptor was obtained by PCR using genomic DNAas template and rTth polymerase (Perkin Elmer) with the buffer systemprovided by the manufacturer, 0.25 μM of each primer, and 0.2 mM of each4 nucleotides. The cycle condition was 30 cycles of 94° C. for 1 min,56° C. for 1 min and 72° C. for 1 min and 20 sec.

The 5′ PCR primer contained a HindIII site with the sequence:

5′-GTGAAGCTTGCCTCTGGTGCCTGCAGGAGG-3′ (SEQ.ID.NO.:1)and the 3′ primer contained an EcoRI site with the sequence:

(SEQ. ID. NO.:2) 5′-GCAGAATTCCCGGTGGCGTGTTGTGGTGCCC-3′.

The 1.3 kb PCR fragment was digested with HindIII and EcoRI and clonedinto HindIII-EcoRI site of CMVp expression vector. Later the cloningwork by Lakaye et al showed that there is an intron the coding rgion ofthe gene. Thus the 5′ end of the cDNA was obtained by 5′ RACE PCR usingClontech's marathon-ready hypothalamus cDNA as template and themanufacturer's recommended protocol for cycling condition. The 5′ RACEPCR for the first and second round PCR were as follows:

(SEQ. ID. NO.:3) 5′-CATGAGCTGGTGGATCATGAAGGG-3′ and (SEQ. ID. NO.:4)5′-ATGAAGGGCATGCCCAGGAGAAAG-3′.

Nucleic acid and amino acid sequences were thereafter determined andverified with the published sequences found on GenBank having AccessionNumber U71092.

Example 3581 Preparation of Non-Endogenous, Constitutively Active MCHReceptor

Preparation of a non-endogenous version of the human MCH receptor wasaccomplished by creating a MCH-IC3-SST2 mutation (see; SEQ.ID.NO.:5 fornucleic acid sequence, and SEQ.ID.NO.:6 for amino acid sequence). Blastresult showed that MCH receptor had the highest sequence homology toknown SST2 receptor. Thus the third intracellular loop (“IC3”) of MCHreceptor was replaced with that of the IC3 of SST2 receptor to see ifthe chimera would show constitutive activity.

The BamHI-BstEII fragment containing IC3 of MCH receptor was replacedwith synthetic oligonucleotides that contained the IC3 of SST2. The PCRsense mutagenesis primer used had the following sequence:

(SEQ. ID. NO.:7) 5′-GATCCTGCAGAAGGTGAAGTCCTCTGGAATCCGAGTGGGCTCCTCTAAGAGGAAGAAGTCTGAGAAGAAG-3′and the antisense primer had the following sequence:

(SEQ. ID. NO.:8) 5′-GTGACCTTCTTCTCAGACTTCTTCCTCTTAGAGGAGCCCACTCGGATTCCAGAGGACTTCACCTTCTGCAG-3′.The endogenous MCH receptor cDNA was used as a template.

Example 3582 GPCR Fusion Protein Preparation

MCH Receptor-Giα Fusion Protein construct was made as follows: primerswere designed for endogenous MCH receptor was as follows:

(SEQ. ID. NO.:9; sense) 5′-GTGAAGCTTGCCCGGGCAGGATGGACCTGG-3′ (SEQ. ID.NO.:10; anitsense) 5′-ATCTAGAGGTGCCTTTGCTTTCTG-3′.The sense and anti-sense primers included the restriction sites for KB4and XbaI, respectively.

PCR was utilized to secure the respective receptor sequences for fusionwithin the Giα universal vector disclosed above, using the followingprotocol for each: 100 ng cDNA for MCH receptor was added to separatetubes containing 2 ul of each primer (sense and anti-sense), 3 uL of 10mM dNTPs, 10 uL of 10XTaqPlus™ Precision buffer, 1 uL of TaqPlus™Precision polymerase (Stratagene: #600211), and 80 uL of water. Reactiontemperatures and cycle times for MCH receptor were as follows: theinitial denaturing step was done it 94° C. for five minutes, and a cycleof 94° C. for 30 seconds; 55° C. for 30 seconds; 72° C. for two minutes.A final extension time was done at 72° C. for ten minutes. PCR productfor was run on a 1% agarose gel and then purified (data not shown). Thepurified product was digested with KB4 and XbaI (New England Biolabs)and the desired inserts will be isolated, purified and ligated into theGi universal vector at the respective restriction site. The positiveclones was isolated following transformation and determined byrestriction enzyme digest; expression using 293 cells was accomplishedfollowing the protocol set forth infra. Each positive clone for MCHreceptor: Gi-Fusion Protein was sequenced and made available for thedirect identification of candidate compounds. (See, SEQ.ID.NO.:11 fornucleic acid sequence and SEQ.ID.NO.:12 for amino acid sequence).

Endogenous version of MCH receptor was fused upstream from the G proteinGi and is located at nucleotide 1 through 1,059 (see, SEQ.ID.NO.:11) andamino acid residue 1 through 353 (see, SEQ.ID.NO.:12). With respect tothe MCH receptor, 2 amino acid residues (an equivalent of 6 nucleotides)were placed in between the endogenous (or non-endogenous) GPCR and thestart codon for the G protein Giα. Therefore, the Gi protein is locatedat nucleotide 1,066 through 2,133 (see, SEQ.ID.NO.:11) and at amino acidresidue 356 through 709 (see, SEQ.ID.NO.:12). Those skilled in the artare credited with the ability to select techniques for constructing aGPCR Fusion Protein where the G protein is fused to the 3′ end of theGPCR of interest.

Example 3583 Assay for Determination of Constitutive Activity ofNon-Endogenous GPCRs

A. Intracellular IP₃ Accumulation Assay

On day 1, cells comprising the receptors (endogenous and/ornon-endogenous) can be plated onto 24 well plates, usually 1×10⁵cells/well (although his umber can be optimized. On day 2 cells can betransfected by firstly mixing 0.25 ug DNA in 50 ul serum free DMEM/welland 2 ul lipofectamine in 50 μl serum-free DMEM/well. The solutions aregently mixed and incubated for 15-30 min at room temperature. Cells arewashed with 0.5 ml PBS and 400 μl of serum free media is mixed with thetransfection media and added to the cells. The cells are then incubatedfor 3-4 hrs at 37° C./5% CO₂ and then the transfection media is removedand replaced with 1 ml/well of regular growth media. On day 3 the cellsare labeled with ³H-myo-inositol. Briefly, the media is removed and thecells are washed with 0.5 ml PBS. Then 0.5 ml inositol-free/serum freemedia (GIBCO BRL) is added/well with 0.25 μCi of ³H-myo-inositol/welland the cells are incubated for 16-18 hrs o/n at 37° C./5% CO₂. On Day 4the cells are washed with 0.5 ml PBS and 0.45 ml of assay medium isadded containing inositol-free/serum free media 10 μM pargyline 10 mMlithium chloride or 0.4 ml of assay medium and 50 ul of 10× ketanserin(ket) to final concentration of 10 μM. The cells are then incubated for30 min at 37° C. The cells are then washed with 0.5 ml PBS and 200 μl offresh/ice cold stop solution (1M KOH; 18 mM Na-borate; 3.8 mM EDTA) isadded/well. The solution is kept on ice for 5-10 min or until cells werelysed and then neutralized by 200 μl of fresh/ice cold neutralizationsol. (7.5% HCL). The lysate is then transferred into 1.5 ml eppendorftubes and 1 ml of chloroform/methanol (1:2) is added/tube. The solutionis vortexed for 15 sec and the upper phase is applied to a BioradAG1-X8™ anion exchange resin (100-200 mesh). Firstly, the resin iswashed with water at 1:1.25 W/V and 0.9 ml of upper phase is loaded ontothe column. The column is washed with 10 mls of 5 mM myo-inositol and 10ml of 5 mM Na-borate/60 mM Na-formate. The inositol tris phosphates areeluted into scintillation vials containing 10 ml of scintillationcocktail with 2 ml of 0.1 M formic acid/1 M ammonium formate. Thecolumns are regenerated by washing with 10 ml of 0.1 M formic acid/3Mammonium formate and rinsed twice with H₂O and stored at 4° C. in water.

Reference is made to FIG. 1. FIG. 1 provides an illustration of IP₃production from several non-endogenous, constitutively activated versionof MCH receptor as compared with the endogenous version of thisreceptor. When compared to the endogenous version of MCH receptor(“MCH-R wt”), MCH-IC3-SST2 evidenced about a 27% increase in IP₃accumulation.

Example 3584 Determination of Compound Using [³⁵S]GTPγS Assay

Direct identification of candidate compounds was initially screenedusing [³⁵S]GTPγS Assay (see, Example 6 of co-pending patent applicationSer. No. 09/826,509). Preferably, an MCH receptor: Gi Fusion Protein wasutilized, according to Example 6(2) of co-pending patent applicationSer. No. 09/826,509. Several lead hits were identified utilizing[³⁵S]GTPγS Assay.

Example 3585 High Throughput Functional Screening: FLIPR™

Subsequently, a functional based assay was used to confirm the leadhits, referred to as FLIPR™ (the Fluorometric Imaging Plate Reader) andFDSS6000™ (Functional Drug Screening System). This assay utilized anon-endogenous version of the MCH receptor, which was created byswapping the third intracellular loop of the MCH receptor with that ofthe SST2 receptor (see Example 2(B)(2) of patent application Ser. No.09/826,509).

The FLIPR and FDSS assays are able to detect intracellular Ca²⁺concentration in cells, which can be utilized to assess receptoractivation and determine whether a candidate compound is an, forexample, antagonist, inverse agonist or agonist to a Gq-coupledreceptor. The concentration of free Ca²⁺ in the cytosol of any cell isextremely low, whereas its concentration in the extracellular fluid andendoplasmic reticulum (ER) is very high. Thus, there is a large gradienttending to drive Ca²⁺ into the cytosol across both the plasma membraneand ER. The FLIPR™ and FDSS6000™ systems (Molecular Devices Corporation,HAMAMATSU Photonics K.K.) are designed to perform functional cell-basedassays, such as the measurement of intracellular calcium forhigh-throughput screening. The measurement of fluorescent is associatedwith calcium release upon activation of the Gq-coupled receptors. Gi orGo coupled receptors are not as easily monitored through the FLIPR™ andFDSS6000™ systems because these G proteins do not couple with calciumsignal pathways.

To confirm the lead hits identified using the [³⁵S]GTPγS assay,Fluorometric Imaging Plate Reader system was used to allow for rapid,kinetic measurements of intracellular fluorescence in 96 wellmicroplates (or 384 well microplates). Simultaneous measurements offluorescence in all wells can be made by FLIPR or FDSS6000™, everysecond with high sensitivity and precision. These systems are ideal formeasuring cell-based functional assays such as monitoring theintracellular calcium fluxes that occur within seconds after activationof the Gq coupled receptor.

Briefly, the cells are seeded into 96 well at 5.5×10⁴ cells/well withcomplete culture media (Dulbecco's Modified Eagle Medium with 10% fetalbovine serum, 2 mM L-glutamine, 1 mM sodium pyruvate and 0.5 mg/ml G418,pH 7.4) for the assay next day. On the day of assay, the media isremoved and the cells are incubated with 100 μl of loading buffer (4 μMFluo4-AM in complete culture media containing 2.5 mM Probenicid, 0.5mg/ml and 0.2% bovine serum albumin) in 5% CO₂ incubator at 37° C. for 1hr. The loading buffer is removed, and the cells are washed with washbuffer (Hank's Balanced Salt Solution containing 2.5 mM Probenicid, 20mM HEPES, 0.5 mg/ml and 0.2% bovine serum albumin, pH 7.4)). One hundredfifty μl of wash buffer containing various concentrations of testcompound are added to the cells, and the cells are incubated in 5% CO₂incubator at 37° C. for 30 min. Fifty μl of wash buffer containingvarious concentration of MCH are added to each well, and transientchanges in [Ca²⁺]i evoked by MCH are monitored using the FLIPR or FDSSin 96 well plates at Ex. 488 nm and Em. 530 nm for 290 second. Whenantagonist activity of compound is tested, 50 nM of MCH is used.

Use of FLIPR™ and FDSS6000™ can be accomplished by followingmanufacturer's instruction (Molecular Device Corporation and HAMAMATSUPhotonics K.K.).

The results were shpwn below.

Compound No. IC₅₀ value (nM) Example 41 6 Example 42 19

It is intended that each of the patents, applications, printedpublications, and other published documents mentioned or referred to inthis specification be herein incorporated by reference in theirentirety.

Those skilled in the art will appreciate that numerous changes andmodifications may be made to the preferred embodiments of the inventionand that such changes and modifications may be made without departingfrom the spirit of the invention. It is therefore intended that theappended claims cover all such equivalent variations as fall within thetrue spirit and scope of the invention.

1. A compound selected from the group consisting of

or a salt thereof.
 2. A compound selected from the group consisting of


3. A compound selected from the group consisting of


4. A compound selected from the group consisting of